A Peer-Reviewed Journal Promoting Science, Clinical Care and Public Health in Sickle Cell Disease and Hemoglobinopathies.

JOURNAL OF SICKLE CELL DISEASE AND HEMOGLOBINOPATHIES

Changing the Conversation for Sickle Cell Disease and Reshaping its FuturePublished: June 7, 2019

JSCDH

Lanetta Bronté-Hall, MD, MPH, MSPHEditor-in-ChiefISSN: 2330-1473 DOI 10.14223

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TOP ABSTRACTS Presenting: Saturday, June 8, 2019 at 5:45 PM

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JSCDH-D-19-00004 OUTCOMES OF OSTEONECROSIS OF THE FEMORAL HEAD IN SICKLE CELL DISEASE AFTER SURGICAL TREATMENT WITH

CORE DECOMPRESSION ALONE VS CORE DECOMPRESSION WITH BONE MARROW ASPIRATE CONCENTRATE INJECTION

Authors: Regina Hanstein, Adele Heib, Irene Chern,

Ugochi O Ugo, Kerry Morrone, Deepa Manwani, Caterina

Minniti, Eric D Fornari, MD

Affiliation: Children’s Hospital at Montefiore

Background: Osteonecrosis of the femoral head (ONFH)

is a common complication of SCD. We set out to describe

clinical and radiographic outcomes of SCD patients with

ONFH treated with (1) core decompression (CD) or (2) CD

plus injection of patients own bone marrow aspirate

concentrate (CD+BMAC). CD involves surgical drilling into

the femoral head to reduce pressure and allow increased

blood flow. The addition of BMAC injection is based on

the hypothesis that BMAC contains osteogenic

precursors, which will repopulate the osteonecrotic

bone.

Methods: 35 hips in 26 SCD patients, 50% female, mean

age 24.3years (range, 9.7-50.7years) at surgery were

evaluated at average follow-up 3.6years (range 0.5-

13years). 30 hips had HbSS/HBSB0 and 5 HBSC/HBSB+.

Demographics, surgical parameters, patient self-reported

pain and ambulatory status were recorded. Femoral head

collapse was assessed on Xrays using the 4-stage Ficat

score system (stage1 pre-collapse → stage4 complete

collapse+flattened contour+decreased joint space).

Results: 17 hips underwent CD and 18 CD+BMAC based

on surgeon preference. All were pre-operatively

transfused to a Hb of 10. In each surgical group, 71%

used Hydroxyurea at time of surgery; CD+BMAC patients

used a higher Hydroxyurea dose compared to CD patients

(18.2mg/kg vs. 25.1mg/kg, p=0.022). Other demographic

and surgical parameters were similar between groups.

Collapse of the femoral head didn’t progress in 8/15 CD

and 9/13 CD+BMAC (p=0.390). Progression to total hip

arthroplasty (THA) was similar between groups: CD 5/17

(29%) vs CD+BMAC 4/18 (22%), p=0.711. Patients

progressing to THA were significantly older at surgery,

used a lower Hydroxyurea dose, and had more pre-

operative femoral head collapse (higher Ficat score)

(Table).

Complication rates in the immediate 6 months period

post-surgery were low; 2 CD and 3 CD+BMAC were

transfused and hospitalization rates for VOC between

groups were similar (p=0.103). With either treatment,

>90% of patients were pain-free and walked

independently at most recent follow-up.

Conclusion: CD and CD+BMAC are safe procedures to

prevent progression of ONFH in SCD patients. Older SCD

patients using lower dosage of Hydroxyurea and more

femoral head collapse were more likely to proceed to

THA.

CD and CD+BMAC No THA THA P-value

Age at Surgery in years, Mean±SD 21 ±9.3 33.9 ±12.0 0.003

Hydroxyurea dose at Surgery in mg/kg, Mean±SD 24.7±4.9 12.5±8.0 0.005

Pre-operative Ficat score, N (%) 1&2

3

4

20 (77%)

3 (11.5%)

3 (11.5%)

3 (37.5%)

5 (62.5%)

0 (0%)

0.042

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JSCDH-D-19-00041 BARRIERS TO THE USE OF ENDARI IN AN URBAN ADULT SICKLE CELL DISEASE CENTER

Authors: 1Ugochi Ogu MD,

1Merin Thomas NP,

2Flo Chan

Pharm D, 1Gracy Sebastian NP, and

1Caterina Minniti MD.

Affiliations: 1 Montefiore Medical Center, 2 Lemed

Pharmacy

Background: In 2017, the US Food and Drug

Administration (FDA) approved Endari (L-glutamine oral

powder) for patients age five years and older with sickle

cell disease (SCD) to reduce disease complications

associated with SCD. This was applauded as the first

medication approval for SCD in almost 20 years, following

Hydroxyurea (HU) in 1998. A phase 3 trial that led to its

approval showed that Endari decreased the number of

pain crisis in SCD patients. We report our experience with

prescribing Endari in an urban adult sickle cell center. To

our knowledge, this report is a first of its kind.

Methods: After prospectively establishing guidelines for

the use of Endari, adult patients with SCD seen in clinic at

a large urban adult SCD center were prescribed Endari via

a local specialty pharmacy, over a 10 month period. Upon

return to clinic, patients were asked about barriers to

obtaining the medication and adherence to the twice a

day dosing. Adherence was also evaluated by calculating

the mean possession ratio (MPR) utilizing pharmacy’s

records.

Results: 101 patients with SCD (58% females, 43% males)

were prescribed Endari over a 10 month period (Table 1):

82% with severe disease genotypes (Hb SS/Sβ0), 18% with

mild genotypes (Hb SC/Sβ+). Mean age was 36 years old.

31% of patients were on concomitant HU and 3% on

chronic transfusions (>6 months). At the end of the 10

month period, 40 patients (40%) were actively taking

Endari, 20 (20%) had discontinued, 35 (35%) never filled

the script, and 6 (6%) had received but never started

Endari. Barriers to initiating Endari included high

deductibles (reported in 7% of patients), denied prior

authorizations (11%) and inability of pharmacy to contact

patient (11%) (Table 2). Reasons for discontinuing Endari

included side effects (46%), poor adherence (22%), no

perceived benefit (20%), and pregnancy (1%) (Table 3).

Average MPR was 0.74, similar to the Endari study.

Discussion: This is the first study that addresses both

acceptance of a new medication by the sickle cell

population and the barriers to obtaining it. We identified

multiple barriers with the initiation and adherence to

Endari in our urban adult SCD patient population. The

most common reason that the medication was not

initiated was denial from the insurance companies. The

most common reason cited for discontinuing Endari was

perceived side effects or ineffectiveness by the patients.

After 10 months, only 40% of patients prescribed Endari

were still taking this medication. As experienced with HU,

several years elapsed from initial FDA approval to its

being more accepted and widely used. From our report, it

is critical to evaluate and eradicate barriers to initiation

and adherence to Endari, to ensure it is readily available

and accessible to the patient population it gained

approval and was intended for.

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Tables 1: Demographics N = 101

Age (mean, range) 36 (21-68)

Sex Female 57 (57%)

Male 43 (43%)

Genotype Hb SS 81 (80%)

Hb SC 12 (12%)

Hb S+ 6 (6%)

Hb S0 2 (2%)

Insurance Medicare/Medicaid 95 (95%)

Private 6 (6%)

Hydroxyurea Yes 31 (31%)

No 70 (70%)

Chronic Transfusion 3 (3%)

Table 2: Barriers to initiating Endari N = 101

High Deductible 7 (7%)

Prior Authorization Denied 11 (11%)

Unable to contact 10 (10%)

Table 3: Reasons for stopping Endari

N = 101

Side Effects 46(46%)

Poor Adherence 22(22%)

Pregnant 1 (1%)

No Perceived Benefits 20 (20%)

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JSCDH-D-19-00046 THE OXYGENSCAN: A RAPID AND REPRODUCIBLE SOURCE OF CLINICALLY RELEVANT

BIOMARKERS IN FOR PATIENTS WITH SICKLE CELL DISEASE

Authors: Celeste K. Kanne3, Minke A.E. Rab

1,2, Brigitte A.

van Oirschot1, Jennifer Bos

1, Maite E. Houwing

4, Marjon

H. Cnossen4 Roger E.G. Schutgens

2, Gerard Pasterkamp

1,

Richard van Wijk1, Eduard J. van Beers

2 and Vivien A.

Sheehan3

Affiliations: 1Laboratory of Clinical Chemistry &

Haematology, University Medical Center Utrecht, 2Van

Creveldkliniek, University Medical Center Utrecht,

Utrecht, The Netherlands, 3Department of Pediatrics,

Division of Hematology/Oncology, Baylor College of

Medicine, Houston Texas, USA,4Department of Pediatric

Hematology, Erasmus Medical Center, Rotterdam, The

Netherlands

Background: In sickle cell disease (SCD), hemoglobin S

(HbS) polymerizes upon deoxygenation, reducing red

blood cell (RBC) deformability. RBC deformability can be

measured over a range of osmolalities and oxygen

concentrations using a Laser Optical Rotational Red Cell

Analyzer (Lorrca) ektacytometer (RR Mechatronics) with

Oxygenscan module (pO2scan). The Oxygenscan

measures 3 key parameters: 1) EImax, RBC deformability

at normoxia; 2) EImin, deformability upon

deoxygenation; and 3) the point of sickling (PoS), the

point at which a >5% decrease in EI is observed during

deoxygenation, reflecting the patient-specific pO2 at

which sickling begins (Figure 1). In this study, we

correlated Oxygenscan parameters with various SCD

genotypes and treatments.

Methods: We analyzed 53 pediatric SCD patients from

Texas Children’s Hospital (TCH) and 24 SCD pediatric and

adult patients from University Medical Center Utrecht

(UMCU). 19 HbSS (median age 5.5 years (y); 10 female

(f)), 11 HbSC (median age 8.9y; 6f), and HbSB+ (median

age 8.4y; 3f) from TCH were analyzed; 14 HbSS patients

without treatment (median age 20.0y; 5f), 6 HbSS

patients with alpha-thalassemia trait without treatment

(median age 9y; 4f), and 3 HbSC patients (median age

28y; 3f) from UMCU were analyzed. To establish

Oxygenscan changes between treatments, we analyzed

RBC from 17 HbSS patients from TCH (median age 10.8y;

6f) on HU before and after transfusion. From UMCU,

samples from 8 patients before and on HU were

analyzed. Tests were performed in duplicate.

Results: In the TCH cohort, PoS differed significantly

between HbSS and HbSC (p<0.01), HbSS and HbSB+

(p<0.0002), and HbSC and HbSB+ (p<0.02). HbSB+

patients tolerated lower oxygen concentrations before

sickling, PoS (23.5 mmHg) than HbSC patients (31.9

mmHg) and HbSS patients (39.9 mmHg). EImin did not

differ between genotypes; EImax did not differ between

HbSS and HbSC, but did between HbSS and HbSB+

(p<0.01), and HbSC and HbSB+ (p<0.000003).

In the UMCU cohort, PoS differed between HbSS and

HbSS + α-Thal (p<0.03) and HbSS and HbSC (P<0.05), with

the lowest PoS in HbSC (mean 47.5 mmHg). HbSS + α-Thal

had a lower PoS (51.1mmHg) compared to HbSS without

α-Thal (67.5 (mmHg).

Transfusion significantly improved the EImax, EImin, and

PoS (p<0.0006, p<0.00004, and p<0.01 respectively). HU

treatment also significantly improved all parameters

compared to baseline (p<0.05).

Conclusion: The Lorrca with Oxygenscan can fully

characterize RBC deformability under a range of oxygen

concentrations. Key measurements - PoS, EImin, and

EImax – were different between genotypes, and changed

significantly with standard of care SCD treatments. We

therefore conclude that these are useful biomarkers of

clinical severity and treatment response, and may be

essential in monitoring novel SCD treatments as part of a

clinical trial.

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ABSTRACT BREAKOUT SESSION I BASIC SCIENCE ORAL PRESENTATION

Presenting: Sunday, June 9, 2019 at 1:45 PM

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JSCDH-D-19-00047 REGULATION OF FETAL HEMOGLOBIN THROUGH THE INSULIN SIGNALING PATHWAY

Authors: Alireza Paikari, Yankai Zhang, Alicia K. Chang, Ankush Goyal, Evadnie Rampersaud, Jonathan M. Flanagan, Mitchell J. Weiss, Vivien A. Sheehan Affiliation: Baylor College of Medicine Background: HbF induction is a key therapeutic strategy

for sickle cell disease (SCD). Analysis of whole exome

sequencing (WES) data from patients with SCD identified

variants in two components of the insulin signaling

pathway, FOXO3 and its activator, AMPK, to be

associated with HbF levels; the association was confirmed

by functional studies in hematopoietic stem and

progenitor cells (HSPC), and metformin, a FOXO3/AMPK

activator, increased HbF in HSPC. Whole genome

sequencing (WGS) analysis identified variants in the

regulatory region of IGFBP3, another component of the

insulin signaling pathway, as associated with HbF levels.

Methods: 658 pediatric SCD patients (>2y, 52% male)

underwent WGS; mixed linear regression was used to

screen for variants associated with %HbF. Three unique

SCD patient-derived HSPC cultures were treated with

metformin (100 µM), compound C (1 µM), and

exogenous IGFBP3 (1µg/ml); their effect on HbF, gamma-

globin, known modifiers of HbF and the FOXO3-AMPK

pathway were assessed by HPLC, RT-qPCR and western

blot at day 14 and 21 of culture. Erythroid maturation

was assessed by morphology and flow cytometry. Plasma

levels of IGFBP3 in patients with and without IGFBP3

variants were measured by ELISA.

Results: WGS identified an association between variants in IGFBP3 and baseline HbF levels (p<1x10

-6). Plasma

IGFBP3 levels were higher in patients heterozygous for an IGFBP3 variant (p=0.01). The role of AMPK in HbF regulation was confirmed by pharmacologic blockade of AMPK by compound C, a specific AMPK inhibitor; compound C reduced gamma-globin expression, and prevented gamma globin induction by metformin.

Treatment of HSPCs with recombinant IGFBP3 resulted in a significant increase in %HbF (p=0.008). Adding IGFBP3 to erythroid culture altered the insulin signaling pathway; total protein levels of FOXO3 increased (p=0.01), as well

as its activated phosphorylated form (Ser 413) that keeps FOXO3 in the nucleus (p=0.03). AMPK protein levels did not increase, but the phosphorylated form of AMPK (Thr172) that in turn phosphorylates and activates FOXO3 did increase (p=0.01). Neither IGFBP3 nor metformin altered erythroid maturation or expression of known gamma globin regulators; BCL11A, KLF1, and MYB.

Conclusions: Unbiased WES and WGS analysis identified

variants in the coding and non-coding region of several

insulin signaling pathway effectors (FOXO3/AMPK and

IGFBP3) to be associated with HbF levels; this was

verified by functional studies in HSPC. We therefore

conclude that the insulin signaling pathway plays a

significant role in gamma-globin regulation and is an

important therapeutic target for HbF induction in SCD

patients.

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JSCDH-D-19-00009

LENTIGLOBIN GENE THERAPY IN PATIENTS WITH SICKLE CELL DISEASE: UPDATED INTERIM RESULTS FROM HGB-206

Authors: Lakshmanan Krishnamurti,

1John F.

Tisdale, 2Julie Kanter,

3Janet L. Kwiatkowski,

4Markus

Y. Mapara, 5Manfred Schmidt,

6Alexandra Miller,

6Francis J. Pierciey,

6Wenmei Huang,

6Jean-Antoine

Ribeil, 7Alexis A. Thompson, and

8Mark C. Walters,

Affiliations:

1National Institutes of Health,

2University of Alabama at Birmingham,

3Children’s

Hospital of Philadelphia, 4Columbia University

College of Physicians and Surgeons, 5GeneWerk

GmbH, 6bluebird bio, Inc.,

7Ann and Robert H. Lurie

Children’s Hospital of Chicago and Northwestern University Feinberg School of Medicine, Blood and Marrow Transplant Program,

8UCSF Benioff

Children’s Hospital Background: β-globin gene transfer into hematopoietic stem cells (HSC) may reduce or eliminate complications of sickle cell disease (SCD). LentiGlobin gene therapy (GT) comprises drug product (DP) made from autologous HSCs transduced with the BB305 lentiviral vector (LVV) encoding β-globin with an anti- sickling T87Q substitution (HbA

T87Q). The safety and efficacy of

LentiGlobin GT in adults with SCD is being evaluated in a phase 1/2 study, HGB-206 (NCT02140554). Patients were initially treated with DP made from bone marrow harvested (BMH) HSCs (Group-A, fully enrolled), then from DP made from BMH HSCs using a refined manufacturing process (Group-B, fully enrolled), and subsequently from plerixafor- mobilized HSCs (Group-C, currently enrolling). Methods: Adults with severe SCD (previously described) were enrolled. CD34+ cells, collected by

BMH or plerixafor (240 µg/kg) mobilization and apheresis, were transduced with BB305 LVV. After myeloablative busulfan conditioning, patients were infused with DP and monitored for safety and efficacy. Summary statistics are median (min—max). Results: As of 15 May 2018, 15 patients were treated with LentiGlobin DP. DP and treatment characteristics are shown in Table 1. DP characteristics were improved in Group-B and Group-C vs Group-A. The safety profile post-DP infusion was consistent with myeloablative conditioning and underlying SCD; most common non-hematologic grade ≥3 AEs were stomatitis, febrile neutropenia, and vaso-occlusive pain. No grade ≥3 DP-related AEs, graft failure, veno-occlusive liver disease, replication-competent lentivirus detection, or clonal dominance were reported. At last visit (Table 1), HbA

T87Q levels were higher in

Group-B (3.2 and 7.2 g/dL) vs Group-A 0.8 (0.5—1.2 g/dL). In 4 Group-C patients at 3-months, HbA

T87Q

(4.1 [3.2—6.0] g/dL) levels were nearly equal to or exceeded HbS levels (3.3 [2.8—3.8] g/dL). In 1 Group-C patient at 6-months, HbA

T87Q was 8.8 g/dL

and total Hb was 14.2 g/dL. Conclusions: These data support the safety and feasibility of plerixafor-mediated HSC collection in patients with SCD. HGB-206 protocol changes have improved LentiGlobin DP characteristics, yielding higher HbA

T87Q levels. Additional data will determine

the clinical effect of increased HbAT87Q

/HbS ratios.

Table 1. DP and Treatment Characteristics

Group-A

(N=7)

Group-B

(N=2)

Group-C

(N=6)

Cell dose (x106 CD34+ cells/kg) 2.1 (1.6—5.1) 2.7 (2.2—3.2) 7.1 (3.0—8.0)

DP vector copy number (copies/diploid genome) 0.6 (0.3—1.3) 3.1 (1.4—5.0) 4.0 (2.8—5.6)

Transduced cells (%) 25 (8—42) 87 (46—95) 81 (78—88)

Neutrophil engraftment (days) 22 (17—29) 26 (23—28) 19 (18—20)

Platelet engraftment (days) 56 (29—63) 46 (31—61) 28 (12—64)*

Follow-up (months) 24.2 (22.8—32.9) 11.4 (8.5—14.3) 3.0 (1.2—6.0)

Values are presented as median (min—max); *n=4 Group-C patients; platelet engraftment was pending in 2 Group-C patients as of data cut

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JSCDH-D-19-00012 VOXELOTOR TREATMENT OF ADULTS AND ADOLESCENTS WITH SICKLE CELL DISEASE:

RESULTS OF THE PHASE 3 HOPE TRIAL

Authors: Elliot Vichinsky1, Carolyn C. Hoppe

2, Jo

Howard3, Kenneth I. Ataga

4, Videlis Nduba

5, Amal El

Beshlawy6, David L. Diuguid

7, Salam Al Kindi

8, Clark

Brown9, Hoda Hassab

10, Paul Telfer

11, Dimitris A.

Tsitsikas12

, Selma Ünal13

, Julie Kanter14

, Miguel R.

Abboud15

, Victor R. Gordeuk16

, Joshua Lehrer-

Graiwer2, Margaret Tonda

2, Allison Intondi

2, Russell E.

Ware17

Affiliations: 1UCSF Benioff Children's Hospital,

Oakland, CA; 2Global Blood Therapeutics, South San

Francisco, CA; 3Guy’s and St Thomas’ NHS Foundation

Trust and King’s College, London; 4University of

Tennessee Health Science Center at Memphis,

Memphis, TN; 5Kenya Medical Research Institute,

Kisumu, Kenya; 6Cairo University, Cairo, Egypt;

7New

York Presbyterian Hospital, Columbia University

Medical Center, New York, NY; 8Sultan Qaboos

University, Muscat, Oman; 9Emory University, Aflac

Cancer and Blood Disorders Center Children's

Healthcare of Atlanta, Atlanta, GA; 10

Alexandria

University, Alexandria, Egypt; 11

Barts Health NHS

Trust, London; 12

Homerton University Hospital NHS

Foundation Trust, London; 13

Mercin University,

Turkey; 14

Lifespan Comprehensive Sickle Cell Center,

Medical University of South Carolina, Charleston, SC; 15

American University of Beirut Medical Center, Beirut,

Lebanon; 16

University of Illinois at Chicago, Chicago,

IL; 17

Cincinnati Children’s Hospital, Cincinnati, OH

Background: Sickle cell disease (SCD) is a genetic disorder caused by a single amino acid substitution in the β-chain of hemoglobin (Hb) resulting in the production of sickle Hb (HbS). When deoxygenated, HbS polymerizes triggering chronic anemia and hemolysis with downstream vaso-occlusive crises and organ damage. Voxelotor is a once-daily oral therapy designed to inhibit hemoglobin (Hb) polymerization, and thereby improve anemia and hemolysis. The randomized phase 3 HOPE study (NCT03036813) evaluates the efficacy and safety of voxelotor in

patients with SCD aged 12 to 65 years. Here we report the results of the pre-specified Part A of the HOPE study.

Methods: Eligible patients were randomly assigned to receive voxelotor (900 or 1500 mg/day) or placebo for ≥24 weeks. The primary endpoint was the proportion of patients with a >1g/dL increase in Hb from baseline at week 24. Secondary endpoints included improvement from baseline in measures of hemolysis (eg, reticulocyte counts and unconjugated bilirubin level) and safety.

Results: Part A included 154 patients with a median age of 25 years (range, 12–59); 14% were adolescents, and 42% were male. Most were HbSS/HbSβ

0: 94% (900 mg), 92% (1500 mg), and

90% (placebo). Hydroxyurea use at study entry was 67% (900 mg), 62% (1500 mg), and 64% (placebo), and median baseline Hb was 8.3 g/dL (900 mg; range, 6.3–10.8), 8.6 g/dL (1500 mg; range, 5.9–10.8), and 8.5 g/dL (placebo; range, 6.1–10.4). At week 24, the percentage of patients with a >1 g/dL increase in Hb from baseline was significantly larger for both voxelotor arms, 900 mg (33%; P=0.0159) and 1500 mg (65%; P<0.0001), compared with placebo (10%). Voxelotor also resulted in improvements in measures of hemolysis, consistent with the demonstrated improvement in Hb. Overall, the treatment-emergent adverse events (TEAEs) were grade 1 or 2 in severity and similar across all treatment groups except for diarrhea, which was higher in both voxelotor arms (900 mg, 19%; 1500 mg, 21%) compared to placebo (10%).

Conclusions: Voxelotor treatment demonstrated a

dose-dependent increase in Hb, with a large number

of patients achieving a >1 g/dL improvement in Hb

and decreases in measures of hemolysis. Voxelotor

was generally well tolerated. Voxelotor has the

potential to be disease modifying by improving

anemia and hemolysis leading to the reduction in

morbidity of chronic organ damage associated with

SCD.

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JSCDH-D-19-00048

A NOVEL NEXT-GENERATION SEQUENCING (NGS) BASED ASSAY FOR NON-INVASIVE PRENATAL TESTING OF SICKLE

CELL DISEASE WITHOUT PATERNAL DNA

Authors: Vivien Andrea Sheehan, Nelda Itzep, MD,

Celeste K Kanne, BS, David Tsao, PhD, Oguzhan Attay,

PhD

Affiliation: Baylor College of Medicine

Background: Over 300,000 infants are born with

sickle cell disease (SCD) every year worldwide,

including at least 1,000 in the US. Prenatal diagnosis

by amniocentesis or chorionic villus sampling is

available; but high cost, invasiveness, and risk of

miscarriage limit their use. Recently, non-invasive

prenatal testing (NIPT), which operate by genetic

analysis of the cell-free fetal DNA (cffDNA) present in

maternal blood, has become commonplace for

aneuploidies, including Trisomy 21. Yet, no NIPT for

SCD or other hemoglobinopathies have been

commercialized to date. We have developed and

optimized NIPT for SCD by assessing the relative

mutation dosage of fetal SCD and beta-thalassemia

DNA through a novel molecular counting strategy

using NGS.

Objectives: The primary objective of this study is to

evaluate the performance of a novel NIPT for sickle

cell disease.

Methods: The SCD NIPT assay and associated custom

bioinformatics analysis were performed on cfDNA

obtained from a training cohort of non-pregnant

compound heterozygotes for SCD. The SCD NIPT assay

was then performed on a validation cohort of

pregnant women with either SCD or sickle cell trait

(SCT). The accuracy of the SCD NIPT was evaluated by

comparison with newborn screening results.

Results: Non-pregnant individuals aged 2-20 years

with genotype HbSE, HbSC, or HbS/beta-thalassemia

were included as a training cohort to establish the

precision and accuracy of the assay for measuring HbS

allele fraction from cfDNA. This cohort had a M:F ratio

of 23:17. As expected, the HbS allele fraction in these

individuals was 0.500 (standard deviation = 0.011, n =

26), and there was no detectable fetal fraction in

these samples. Both training and validation cohort

results matched the theoretical limit of detection set

by the number of cell-free HBB DNA molecules in

plasma. The precision and accuracy of the HBB assay

on cfDNA were then used in conjunction with >1000

pre-clinical samples (mixtures of sheared SCT and SCD

genomic DNA) to determine analytical sensitivity

>98% and specificity >99%, even in the absence of

paternal DNA.

Conclusion: We have developed an assay for NIPT of

sickle cell disease. The results obtained to date

indicate that the assay reliably detects fetal SCD

status when the fetal fraction is as low as 5%, the

same limit as aneuploidy NIPT. SCD NIPT could be

particularly useful for deciding to bank umbilical cord

blood as a source of stem cells for future gene-editing

cures.

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JSCDH-D-19-00049 CLINICAL TRANSFORMATION IN CARE FOR PATIENTS WITH SICKLE CELL DISEASE AT AN URBAN ACADEMIC

MEDICAL CENTER

Authors: Sanaa Rizk, MD, David Axelrod, MD, Gaye Riddick-Burden, CRNP, Elisabeth Congdon-Martin, LSW, Steven McKenzie, MD, Carol Haines, John McAna, PhD, Albert G. Crawford, PhD, Lawrence Ward, MD

Affiliation: Thomas Jefferson University Hospital

Abstract:

Background: Sickle cell disease (SCD), an inherited red blood cell disorder, is characterized by anemia, end-organ damage, unpredictable episodes of pain, and early mortality. Emergency department (ED) visits and hospitalizations are frequent, leading to increased burden on patients and increased health care costs. We report herein on two clinical transformations at Thomas Jefferson University Hospital in care for patients with SCD over the past 6 years. The first clinical transformation, in November 2013, was a multidisciplinary care team intervention which included monthly team meetings and development of individualized care plans and targeted for management of uncomplicated pain crises. The second clinical transformation, in 2015, involved changing the locus of care from a dedicated Sickle Cell day unit to an approach which “fast-tracks” patients through the ED into an observation unit with 24/7 access.

Methods: This study assessed the two clinical transformations mentioned above. The effects of the first clinical transformation were assessed through

quantitative statistical analyses, stratified by high utilizer status (already reported in a manuscript published in the American Journal of Medical Quality

1). The effects of the second clinical

transformation were assessed through both quantitative statistical analysis and qualitative analysis, i.e., five case studies.

Results: Regarding the first clinical transformation, following implementation of the multidisciplinary care team intervention, significant decreases in both ED and inpatient utilization were identified among those individuals with a history of high ED utilization. Regarding the second clinical transformation, quantitative analyses of claims data suggest further decreases in the rates of ED visits and inpatient stays, but these analyses require further refinement. At the same time, five case studies reinforce the overall findings and provide insight into the specific effects of the clinical transformation on the course of patients’ SCD and other comorbid conditions, and also their quality of life.

Conclusions: Findings highlight the potential strength of these clinical transformations.

Reference: 1Powell RE, Lovett P, Axelrod D, Crawford A, McAna J,

Ward L, Pulte E. A multi-disciplinary approach to impact acute care utilization among individuals with sickle cell disease. American Journal of Medical Quality, 2018, 33(2),127-131.

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ABSTRACT SESSION I- HEALTH SERVICES ORAL PRESENTATIONS

Presenting: Sunday, June 9, 2019 at 1:45PM

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JSCDH-D-19-00014 THE ROLE OF SOCIAL DETERMINANTS OF HEALTH IN AFFILIATION STATUS FOR A COHORT OF SICKLE CELL DISEASE

PATIENTS FROM A CHICAGO BASED COMPREHENSIVE SICKLE CELL CENTER

Authors: G.G. Méndez, V. Gordeuk, M. Berbaum, J.M. Nocek, L.L. Hsu.

Affiliation: University of Illinois at Chicago College of Medicine

Background: Factors associated with clinic

attendance are better understood for children with

sickle cell disease (SCD) than for adults with SCD. We

used a definition for unaffiliated patients developed

by the NIH Sickle Cell Disease Implementation

Consortium (SCDIC): those who have had no

appointments with a SCD expert in the non-acute

setting in 2 years. In our previous examination of an

administrative dataset, unaffiliated SCD patients (15-

45 years of age) were more likely to be uninsured and

were lower utilizers of acute care services than

affiliated patients, but surprisingly had fewer

recorded comorbidities. These findings are consistent

with socio-ecological factors exerting an influence on

the health of SCD patients. The Distressed

Communities Index (DCI) for a zip code is a marker for

a community’s socio-demographic and socio-

economic status (Economic Innovation Group,

Washington DC).

Hypothesis: Unaffiliated SCD patients are more likely

than affiliated patients to live in zip codes with high

DCI.

Methods: A retrospective review compared affiliated

and unaffiliated Chicago patients in the SCDIC

Registry. Each patient’s zip code was used to look up

the 2016 DCI. DCI ranges from 0 to 100 and the worst

quintile is termed “most distressed” (80-100).

Results: Of 299 patients (58% female; mean age 30.0)

who met the inclusion criteria, 56 (46.0% female;

mean age 30.0) met the definition for unaffiliated. No

difference in distress score between affiliated and

unaffiliated SCD patients was observed, with 58% of

the affiliated and 59% of the unaffiliated residing in

the most distressed zip codes (P>.9, by Mann-

Whitney U test).

Conclusions: In our Chicago sample, the percentage

of patients in the high distress category (DCI 80-100)

was the same for affiliated and unaffiliated (58% to

59%). Nationally, (26.9% to 35%) of African-Americans

are in distressed communities. The findings reinforce

previous reports that SCD is correlated with

socioeconomic disadvantage. To overcome the

sample bias from a SCD center whose mission is to

provide care for the underserved, similar analyses

could be conducted in SCD centers that serve a

broader population of sickle cell patients. In addition,

a limitation of this study is that the unaffiliated SCD

patients were identified from a healthcare source and

may not be representative of all unaffiliated patients.

Acknowledgements: SCDIC has been supported by US

Federal Government cooperative agreements

HL133948, HL133964, HL133990, HL133996,

HL133994, HL133997, HL134004, HL134007, and

HL134042 from the National Heart Lung and Blood

Institute and the National Institute on Minority Health

and Health Disparities (Bethesda, MD), plus U01

HL134042-3S2 from NHLBI Research Supplements to

Promote Diversity in Health-Related Research for

Gustavo G. Mendez.

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JSCDH-D-19-00020 SYSTEMATIC DESIGN AND REVISION OF A MOBILE APPLICATION FOR ENHANCING ADHERENCE TO PRESCRIBED

OPIOIDS IN SICKLE CELL DISEASE

Authors: Daniel Sop1, 2 *

, Wally Smith1, Azhar Rafiq

3,

Abdulkhaliq Alsalman1, Donna McClish

4, Shirley

Johnson1, Thokozeni Lipato

1, Taylor Elliott

1 and Ding-

Yu Fei2

Affiliations: 1Department of General Internal

Medicine, 2Department of Biomedical Engineering,

3Department of Surgery, and

4Deptment of

Biostatistics, Virginia Commonwealth University,

Richmond, VA 23298, USA

Introduction: Sickle cell disease (SCD) is the most

common inherited blood disorder that produces a

progressively disabling illness with severe clinical

consequences. A significant portion of patients with

SCD use prescribed opioids regularly. In order to

safely start, adjust, taper, and stop opioids clinicians

need better tools to follow or trend the opioid use

pattern. Thus, the goal of this study was to develop

and test the feasibility of a mobile application for

adherence to prescribed opioids, and capture

context-specific data associated with prescription

opioid use.

Methods: The designated OpPill Mobile Application

development was carried out to reflect the needs of

the SCD community, and allow for information input

related to concerns gathered from the focus group.

The overarching software requirements for the app

included:

• Easy-to-use and intuitive graphical interface• Functional parameters to allow

documentation of medication adherence andsymptomology

• Data transmission and storage capabilitiesmeet HIPAA requirements

• Multi-platform capability to ensure appeffectiveness across diverse mobile devices

Each phase of the app development was subjected to

continuous expert reviews, and validation of the

software through iterations of Low Fidelity Testing.

Functional relevance of the software was measured

with focus group surveys, which consisted of in-

person interviews. The interviews were audio-

recorded and transcribed for qualitative analysis.

Results: Approximately 57% (n=12) of the participants

were women. Focus group members ranged in age

from 18 to 58 years, with more than half (57%) of the

participants possessing the SS genotype of SCD.

Qualitative thematic analysis from interviews

revealed three phenomena: 1) SCD patients exhibited

various opioid-consuming behavior patterns including

adherence, overuse, underuse, and erratic use; 2)

Several biopsychosocial factors hindered or motivated

opioid use: severe pain intensity, side effects, stress,

family gatherings, unplanned meetings, religious

attendance, and anticipatory fear adverse outcomes;

3) Behaviors varied based on the time of day, week,

month, or year, and also based on the momentary

contexts at times of actual and projected doses.

Conclusion: The presented OpPill app was developed

as a specific tool for the documentation of medication

adherence by SCD patients. The process and outcome

of the study for the development of the app

demonstrates a mobile-health model for effective

SCD management in alignment with current clinical

practice.

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JSCDH-D-19-00033 SEVERITY AND BURDEN OF SICKLE-CELL DISEASE IN FRANCE: RESULTS FROM THE NATIONAL HOSPITAL DISCHARGE

DATABASE OVER A 7 YEARS FOLLOW-UP.

Authors: Bernard Dauvergne2, Cheikh Tamberou

1,

Valérie Trouillet Poujol1, Carlosse Keumeugni

2, Maryse

Etienne-Julan3, Frédéric Galacteros

4

Affiliations: 1 Sirius-Customizer, 7 rue des Filles du Calvaire, 75003 Paris 2 Addmedica, 37 Rue de Caumartin, 75009 Paris 3 CHU de Pointe à Pitre, Abymes, route de Chauvel, 97159 Pointe à Pitre 4 CHU Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil Background: PMSI is an exhaustive French hospital discharge database covering all overnight or day hospitalizations used by all health facilities. SCD management is mainly linked with admission in intensive care unit (ICU), full or partial hospitalizations.

Objective: The aim of the study was to estimate the number of hospital admissions, to determine the SCD severity and its trend, to analyze the hospital burden in terms of total number of stays, total number of hospital days, and frequencies of readmissions in the database from 2009 to 2016.

Method: A cohort of patients identified in 2009 with the following ICD-10 codes of SCD as primary or associated diagnoses: D57.0 (sickle-cell anemia with crisis), D57.1 (sickle-cell anemia without crisis), and D57.2 (double heterozygous sickling disorders) has been followed over the period 2009 to 2016. All related SCD hospitalizations have been collected. SCD severity for a given patient have been defined by the occurrence of at least one of the following cumulative

events occurring since the year of admission and observed over a 12 month-period: (1) at least 3 distinct admissions, (2) 8 or more transfusions, (3) a total of 10 or more days at hospital, regardless of the number of distinct admissions.

Results: 8,695 (46% females and 54% males) SCD patients were hospitalized in 2009, 51% were above 18 of years and 49% below, out of 581 were under 2 years of age (Table 1).

More than 60% of the patients has been re-hospitalized within the first year following inclusion and 80% at least once during the 7 years-follow up.

Patients under 18 years were much more re-hospitalized (90% vs 72% p=0,0001).

Averages of 5 and 21 hospitalizations per patient are observed after respectively one year of follow up and at the end of period.

50% of the admissions were full hospitalizations, 43% were identified with a diagnosis of SCD crisis and nearly 30% of them were first admitted in ICU. (Table 2)

Around 60% of the patients were severe at least once during the follow-up period (Table 3)

Conclusion: Sickle cell patients are young and severe and readmissions are frequent. It is interesting to note that a significant part of the patients presents a period of severity and in this opposite over a 7-years period, 20% of them remain free of hospitalization. Moreover, this study highlights how the French PMSI system can be used for epidemiological analyses.

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Table 1: Re-admissions after 12 month-follow up and at the end of the follow up period (2009-2016)

Age Number of

patients Re-admissions within

365 days Re-admissions in the follow

up period (2009 à 2016)

[00 , 02[ 581 61% 80%

[02 , 05[ 786 67% 90%

[05 , 10[ 1 185 68% 93%

[10 , 18[ 1 535 71% 91%

[18 , 30[ 2 073 62% 78%

[30 et +[ 2 535 46% 68%

Total population 8 695 60% 81%

Age < 18 4 445 53% 72%

Age > 18 4 250 68% 89%

Table 2: Patient care pathway

Number of stays

Number of stays per patient

% of admission in

ICU

% full hospitalizations

% of stays with crisis

After 1 yr-follow up 41 048 5 27,6% 50,3% 43,4%

After 7 yrs-follow up 185 346 21 27,0% 41,2% 43,7%

Table 3: Numbers of severe cases by severity criterion during the follow up period

Age Number of

patients

At least 3 distinct admissions in 12

months

8 or more transfusions in 12 months

10 days of full hospitalizations in

12 months

Severity composite criterion

(at least 1 of the 3 criteria)

[00 , 02[ 581 53% 14% 51% 62%

[02 , 05[ 786 53% 16% 56% 66%

[05 , 10[ 1 185 51% 17% 56% 65%

[10 , 18[ 1 535 52% 14% 58% 66%

[18 , 30[ 2 073 46% 12% 59% 64%

[30 et +[ 2 535 29% 11% 48% 52%

Total patients 8 695 44% 13% 54% 61%

Age < 18 4 250 52% 15% 56% 65%

Age > 18 4 445 36% 11% 53% 57%

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JSCDH-D-19-00023 ESSENTIAL FEATURES FOR SICKLE CELL DISEASE PATIENTS AND UTILIZATION OF COMMUNITY HEALTH WORKERS

Authors: Joan Corder-Mabe, RN, MS; Shirley Johnson, BA,LSW; Daniel Sop, MS; Taylor Elliott, MSW; Wally R. Smith, MD Affiliations: Virginia Commonwealth University Background: Numerous titles are utilized for CHW’s

that often will misrepresent their similar roles in

assisting patients with chronic disease. Therefore, we

use an evidence review and consensus to advance a

common framework and uniform definition of the

functions of CHW’s, which identifies differentiated

CHW roles and responsibilities. The justification for

these roles offers support for certification,

credentialing, education, licensure and payment for

services performed by CHW’s.

Methods: During a recent study funded by the NHLBI”

Start Healing in Patients with Hydroxyurea (SHIP-

HU)”a randomized controlled trial , using synthesized

consensus reports and analysis was used to validate

the efficacy of CHW’s. In order to codify this evidence

according to CHW occupational activities, we

performed a rapid, narrative and tabular review of

the CHW literature, including clinical trials, met an

analyses and policy reports summarizing over 200

CHW interventions to improve patient health status

or care delivery. We tabulated a numeric frequency

count of specific roles, responsibilities, competencies,

and behaviors utilized in these interventions, using a

predetermined list built from a review of all the

included interventions.

Results: (Table) A set of recommendations included

content for formal codification of the CHW

profession. Our findings suggest that the more

frequent CHW behaviors might be more important or

generally required of all CHWs, whereas the rarer

behaviors might either be more specialized or might

be less often required of all CHWs. We propose a

common framework or taxonomy consisting of four

levels of CHW function: Peer Community Health

Worker (PCHW), General Community Health Worker

(GCHW), Clinical Community Health Worker (CCHW),

and Health Navigator (HN). Throughout the reviews,

the CHW’s displayed effective culturally competent

health education to individuals and groups, as well as

health system navigation and care coordination. The

literature also did not display strong evidence

supporting the efficacy of CHW’s in the provision of

direct services. Supervision and support were

frequently indicated but not universally mentioned.

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Core Competencies

Functions (Behaviors/Interventions

Demonstrated Competencies)

Total

frequency of

function by

source (n=309)

Health system navigation and care coordination

(Service coordination, patient navigation, linkage

to resources, information on community

resources

Assist patient make physician/medical

appointment.

14

Assist patient understand, obtain or use

health insurance.

2

Arrange child care, transportation, or

translation services.

8

Follow-up on missed health

appointments

17

Link patient with local resource services

such as assistance with transportation or

meals.

41

Make appointment telephone calls or

send reminders by mail.

55

Refer to local resources to help meet

medical and psychosocial needs.

18

Coaching and social support (Bridging cultural

mediation, Building trust, Emotional support,

Cultural mediation, Home-based support,

Cultural linkage, Cultural liaison, One-on-one

counseling, Informal counseling)

Make phone calls to elicit patient

concerns or to discuss health status.

4

Discuss patient’s experiences with the

health care system.

8

Refer to or lead support groups. 5

Model behavior change. 41

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Provide informal counseling and

emotional support.

76

Conduct discussions with patient about

their health status, fears or feelings

about having a chronic disease or life-

threatening event.

12

Culturally competent health education (Health

promotion, Peer education, Outreach education)

Provide education about a specific

disease or health condition to individuals

or groups.

107

Provide cultural insights to health care

team.

4

Provide information regarding general

health maintenance such as diet,

exercise and health screening

recommendations.

29

Direct service (Serve as member of health care

team, Communication with provider and/or

health care team, Liaison with health care

delivery system, Bridge between health care

provider and patient)

Assist in taking prescribed medication or

adhere to medical treatment

16

Monitor patient’s vital signs such as

blood pressure or blood sugar testing or

conduct health screenings.

23

Assist meeting basic needs such as food,

shelter, first aid, and housing.

6

Assist patient develop health goals and

appropriate action steps.

10

Help patient apply for health insurance

or other financial aid.

3

Encourage patients about health lifestyle

changes such as weight management,

routine health screenings, or exercise.

12

Notify and assist in the immunization of

children.

4

Accompany patient to medical 2

23 | P a g e

appointments

Communicate relevant patient

information to the health care team

including documentation on medical

record.

8

Participation in evaluation and research

(Individual or community assessments)

Collect data regarding patient health

status for a program or research project.

9

Engage persons as participatory research

partners.

3

Assist in community needs assessment

and assessment of population data.

6

Conduct environmental assessments. 1

Provide computerized data entry and

conduct web searches.

1

Advocacy (Individual and/or community capacity

building, Community mobilization, Community

organizer)

Advocate for community needs or

address specific issues such as living

conditions.

20

Be spokesperson or intermediaries

between clients and organized medicine

or bureaucracies.

11

Teach the patient effective

communication skills so they can have

productive interactions with medical

personnel.

3

Provide translation and/or

interpretation services.

7

Outreach and case-finding (Eligibility and

enrollment)

Recruit participants into a program or

service.

23

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Assist patient enroll in program or

service

12

Prepare and distribute materials. 14

Promote health literacy 2

Conclusions: The evidence-based CHW

taxonomy definitions provides four categories

that best describe CHW’s in which to place

workers and established appropriate guidelines

for the level of services that can be provided and

if tested, validated and adopted.

JSCDH-D-19-00015 EPIDEMIOLOGY OF SICKLE CELL DISEASE (HBSS) IN US MEDICAID ENROLLEES

Authors: Rishi J. Desai, MS, PhD;

1 Mufaddal Mahesri,

MD, MPH;1 Raisa Levin, MS;

1 Denise Globe, PhD;

2

Krista McKerracher, MBA;3 Alex Mutebi, PhD;

2

Rhonda Bohn, MPH, ScD;4 Maureen Achebe, MD,

MPH;5 Sebastian Schneeweiss, MD, ScD

1

Affiliations: 1 Division of Pharmacoepidemiology and

Pharmacoeconomics, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA, USA

2 Vertex

Pharmaceuticals Inc, Boston, MA, USA 3 CRISPR

Therapeutics, Boston, MA, USA 4 Bohn Epidemiology,

Boston, MA, USA 5

Hematology Division, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA, USA.

Background: Sickle cell disease (SCD) is a recessive hereditary disease, caused by a mutation in the β-globin gene. Overall, SCD most commonly affects African Americans (AA). A substantial number of SCD patients are covered under the US Medicaid program as the disease can significantly impact functioning and the ability to maintain employment. Because of a paucity of contemporary data, this study was designed to estimate the prevalence of SCD (HbSS) among US Medicaid enrollees.

Methods: Administrative claims data from US Medicaid programs were analyzed (2000 – 2012) to characterize the epidemiology of SCD (HbSS). We assembled annual cohorts of Medicaid enrollees across 13 years to estimate prevalence. Diagnosis codes for HbSS (ICD-9 codes of 282.61 and 282.62) were used to identify patients with SCD in each annual cohort. Crude and age- and race-stratified prevalence estimates with 95% confidence intervals (CI) per 100,000 were generated.

Results: The analysis included annual cohorts ranging from 13,629 cases out of 17.2 million Medicaid enrollees in 2000 to 21,781 cases out of 35.7 million Medicaid enrollees in 2012. There were notable changes in the racial/ethnic distribution of Medicaid enrollees over the years; between 2000 and 2012 the percentage of African American (AA) enrollees decreased from 32.6% to 24.8%, while Hispanics increased from 19.0% in 2000 to 26.5% in 2012. The overall crude prevalence (95%CI) of SCD (HbSS) in the Medicaid program decreased from 79.1/100,000 (77.8-80.4) in 2000 to 61.0/100,000 (60.1-61.8) in 2012. Prevalence (95% CI) in the AA enrollees ranged from 203.2/100,000 (199.5-207.0) in 2000 to 199.2/100,000 (196.2-202.1) in 2012. The highest prevalence was noted in 18-35 year old AAs, which decreased from 421.4/100,000 in 2000 to 317.9/100,000 in 2012. The birth prevalence (among those with age <1 year) was 132.8/100,000 in 2000 and increased to 177.5/100,000 in 2012 among AAs and was substantially lower among Caucasians and Hispanics (3.9 and 9.8 per 100,000 in 2012, respectively).

Conclusion: While the overall prevalence of SCD (HbSS) in Medicaid appeared to decrease over the years, the disease remains majorly prevalent in AAs especially among 18-35-year-olds, suggesting a substantial burden of disease and unmet need. These results provide the most contemporary estimates of the prevalence of SCD (HbSS) in the US. These findings can inform resource allocation and disease-focused initiatives to address this unmet need.

Sponsored by Vertex Pharmaceuticals Incorporated

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JSCDH-D-19-00062

USING PROJECT ECHO TO MEET THE NEEDS OF PATIENTS WITH SICKLE CELL DISEASE

Authors: Gail Gutman MD, Megan Rees MD, Toni DeNicola PNP, Jeffrey Gershel MD, Kenneth Rivlin MD Affiliation: Department of Pediatrics, Jacobi Medical Center, NYC Health+Hospitals Background: Sickle cell disease (SCD) is a serious chronic disease affecting approximately 100,000 people in the United States. The American Society of Hematology (ASH) has defined four priorities when addressing SCD healthcare inequities: (1) Access to Care in the United States, (2) Training and Professional Education, (3) Research and Clinical Trials, and (4) Global Issues. We believe that Project ECHO (Extension for Community Healthcare Outcomes) can be an effective model to address these priorities. Project ECHO was developed to improve the treatment of hepatitis C in rural, underserved New Mexico. Employing videoconferencing with specialists, remote primary care providers (PCPs) presented patients, received guidance, and had patient outcomes equal to those who directly saw specialists. This approach of “tele-mentoring” has made significant differences in many complex diseases, from asthma to Zika. Our objective is to review the literature and discuss current and future applications of Project ECHO in the care of patients with SCD. Methods: The ECHO Institute maintains a database of all peer reviewed papers, editorials, reports, and projects that have used their model of tele-mentoring. We examined these resources and identified applications appropriate for the ASH-defined priorities.

Results: From the start of Project ECHO in 2003, until February 2019, there have been 147 peer-reviewed papers addressing 26 different medical conditions. Most of these studies focused on (1) improving access to care and (2) professional training/education, while some have addressed (3) research through quality improvement/implementation science, and others have demonstrated the (4) model’s global potential. Driven by the Health Resources and Services Administration’s Sickle Cell Treatment Demonstration Project, the number of SCD ECHOs is increasing. Most address priorities (1) and (2) through mentoring PCPs. Other SCD ECHOs are concerned with eliminating inequities through quality improvement/implementation research (3). These ECHOs establish and support registries, transition of care programs, medical homes, SCD-appropriate emergency care, and community health workers. The World Health Organization has recognized the value of ECHO. Yet, as of February 2019 there were no global SCD ECHOs, despite ECHO’s role for other diseases in countries with the highest prevalence of SCD. Conclusion: SCD is characterized by inequities in healthcare quality, funding, and research. In the United States and elsewhere, Project ECHO is effective for many complex medical conditions. Its application to SCD is just beginning but it has the potential to address all 4 of ASH’s priorities for sickle cell disease.

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ABSTRACT BREAKOUT SESSION I PSYCHOSOCIAL ORAL PRESENTATION

Presenting: Sunday, June 9, 2019 at 1:45PM

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JSCDH-D-19-00064

HEALTH-RELATED FACTORS PREDICT ADAPTIVE FUNCTIONING PROFILES IN

YOUTH WITH SICKLE CELL DISEASE

Authors: Megan Loew, PhD, Mary Keenan, BA,

Rebecca Rupff, BA, Jamilla Griffith, MSW, Kathryn

Russell, PhD, Jerlym Porter, PhD, MPH

Affiliations: Virginia Commonwealth University

Background: Youth living with Sickle Cell Disease

(SCD) face health-related and life stressors. These

psychosocial factors may impact youth adaptive

functioning such as self-esteem and interaction with

others. Limited research examines adaptive

functioning and related psychosocial, disease, and

demographic factors in this population. The purpose

of this study is to empirically develop adaptive

functioning profiles that describe subgroups among

youth living with SCD, and to determine if life

stressors, age, gender, hospitalizations, and SCD

genotype predict the subgroup membership.

Methods: Participants were 194 youth with SCD aged

8-17 years recruited for a larger study examining SCD

(Mage=13±2.9 years; 52% female). Youth completed

the Behavioral Assessment System for Children

(BASC-2), which includes four adaptive functioning

subscales (relations with parent, interpersonal

relations, self-reliance, and self-esteem), higher

scores indicate higher functioning. Youth’s age,

gender, SCD genotype, and number of

hospitalizations were obtained from medical records.

Latent profile analyses (LPA) developed profile

descriptions based on the BASC-2 subscales. Log of

the odds ratio (LogO) with a p < .05 was considered

significant.

Results: LPA revealed four distinct adaptive

functioning profiles: 1) High overall adaptive

functioning (n=109; 56.19%) with scores ranged

(56.15-58.54); 2) High interpersonal and self-esteem

(n=58, 29.90%) with scores ranged (41.94-55.05); 3)

High relations with parents and self-esteem (n=11,

5.67%) with scores ranged (29.22-52.01); and 4) High

interpersonal (n=16, 8.25%) with scores ranged

(32.07-50.12). Experiencing less stress increased the

likelihood of being in the High overall (LogO=.314,

p=.003) or High relations with parents and self-

esteem (LogO=.358, p=.002) groups compared to the

High interpersonal group. Male gender identity

increased the likelihood of being in the High

interpersonal and self-esteem group (LogO=1.22,

p=.013) compared to the High overall group. Being

hospitalized in the last 3 years increased the

likelihood of being in the High interpersonal group

(LogO=1.66, p=.051) compared to the High overall

group. Older age increased the likelihood of being in

the High overall adaptive functioning group

(LogO=.305, p=.020) compared to the High

interpersonal strengths group. SCD genotype was not

a significant group predictor.

Conclusions: The majority of our sample reported

overall high adaptive functioning. Distinct patterns of

all four adaptive functioning profiles were predicted

by stress in youth with SCD. Age and female gender

significantly predicted membership in the High overall

adaptive functioning group. Self-esteem, child-parent

relations, and interpersonal skills uniquely contribute

to adaptive group membership. Findings support

examining the impact of stress on adaptive

functioning at an early age in this population.

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JSCDH-D-19-00057 CARE FOR PHYSICAL ACTIVITY AND SICKLE CELL DISEASE: WHAT IS THE KNOWLEDGE OF TEACHERS IN FITNESS

CENTERS AND SCHOOLS IN NORTHEAST BRAZIL?

Authors: Lea Barbetta, Silva Evanilda Souza Carvalho, PhD, Ivanilde Guedes Mattos, Raissa Lago, Helaynne Bezerra Nascimento, Raiotelma Lopes Silva Affiliations: State University of Feira de Santana Northeastern Brazil stands out because of the high prevalence of sickle-cell disease, with Bahia, the state with the largest black population in the country and also the highest incidence of SCD, with approximately 5.5% of the population affected the disease. In the period from 2008 to 2014, 8,103 hospitalizations for sickle cell anemia complications were registered in the state health system, proving to be a serious public health problem. Advances in the clinical treatment and improvement of the general physical state of the sick people represented gain in the components of the physical fitness and greater tolerance to physical efforts, providing autonomy for execution of the daily tasks, has allowed the insertion and participation which for children and adolescents in physical activities developed in fitness centers and schools. A cross-sectional, exploratory study was carried out with the objective was to verify the knowledge of physical education teachers about sickle cell disease and care in the gymnasium and elementary school classes in Feira de Santana, a city in the semi-arid

region of Bahia, with an average of 4 sickle cell disease cases per 10,000 inhabitants. The data collection was performed using a self-administered questionnaire with multiple choice questions about participants' characteristics and knowledge about sickle cell disease, and a question about the care of these individuals. The data were treated with descriptive statistics and the project was approved by the Research Ethics Committee of the National Health Council. The study was attended by 115 teachers, 80 of whom were linked to 15 fitness centers and 35 linked to the 17 public primary schools in the region. The results showed that most of the teachers knew about the disease, but this knowledge was not sufficient to guarantee safety in the care of the patients who were ill at the sites investigated. Another important finding was that in most schools there was no record of any aspects related to student health. Regarding the care provided in the classes, the teachers reported that they were worried control of the intensity of activities, rest in moments of fatigue, monitoring of the use of prescribed medications and hydration. The physical education teachers demonstrated not know about sickle cell disease and its implications enough. The physical activities so desired by young people always have been avoided because of the insecurity these professionals

.

Table 1. Characteristics of physical education teachers of fitness centers and schools in the Northeast of

Brazil, 2016-2018.

Participants n %

Total 115 100

Gender

Female 31 26,9

Male 84 73,0

Formation

Students 44 38,2

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Graduates 39 33,9

Post graduates 32 27,8

Source: Direct search

Table 2. Knowledge of physical education teachers about sickle cell disease in Northeast of Brazil, 2016-

2018.

Yes No No

answer

n % n % n %

Have you ever heard of sickle cell disease?

85 73,9 29 25,2 1 0,8

35 30,4 73 63,4 7 6,0

Is the information you have about this disease acquired during your

undergraduate course?

35 30,4 75 65,2 5 4,3

Dou you make any special arrangements for this student?

3

2,6 46 40 66 57,3

Does the fitness centers have initial physical assessment for your

students?

69 86,2 11 13,7 0 0

Does the school have any records on the health aspects of the

students?

11 31,4 24 68,5 0 0

Source: Direct search

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JSCDH-D-19-00040 STIGMA OF PAIN AND SICKLE CELL DISEASE IN BAHIA – BRAZIL

Authors:

1Jayanne Moreira Carneiro,

1Sheila Santa

Barbara Cerqueira, 1Aline Silva Gomes Xavier,

1Evanilda Souza de Santana Carvalho,

2Coretta Melissa

Jenerette Affiliations:

1Universidad Estadual de Feira de

Santana, 2College of Nursing University of South

Carolina Background: Although Bahia is the state with the largest population with sickle cell disease in Brazil, the sick people find barriers to their care that reveal the need for investment in interventions to overcome stigma. This study aiming to understand the stigma experienced by people with sickle cell disease (SCD), in Bahia-Brazil. Methodology: We developed a qualitative study, 120 people, 52 males and 68 females, with SCD resident in the capital and in the interior of the state of Bahia responded to interviews, which were then submitted to content analysis. Results: The results show that in the family environment, people with SCD are charged to perform activities that are incompatible with their

tolerance, and when they do not, they are criticized and seen as incapable or useless resulting in abandonment by relatives in times of crisis. In the general public they are perceived as lazy and unproductive, incapable of working. In all the scenarios the discredit of the pain reports occurs. And in the health units the experiences of stigma are crossed by institutional racism where professionals nurture the stereotype of the slave and strong black, who supports everything, leading to delays in care, discourteous service or physical and psychological abuse. Conclusion: It is necessary to overcome the invisibility of the disease, to clarify doubts of the public, to demystify beliefs that put the sick person in a condition of depreciation, as well as to sensitize the family about the physical and psychoemotional limitations that pain produces on the person with SCD. In the context of health services, there is an urgent need to qualify professionals about SCD at different levels of health care so that they recognize pain as one of the complications of the disease and are able to assess and treat the pain episode, understanding that it constitutes a clinical emergency.

Figure 1 Aspects of stigma of pain and its coping by people with sickle cell disease

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JSCDH-D-19-00005 THE ROLE OF DIETARY SELENIUM AND GPX1 IN THE PATHOPHYSIOLOGY OF SICKLE CELL DISEASE

Authors: Ramasamy Jagadeeswaran

1,, Vinzon Ibanez

2,5, Lenny K. Hong

3, Robert E. Molokie

2,4,5, Alan M.

Diamond3,4

, Angela Rivers1,5

Affiliations: 1Department of Pediatrics, 2Department

of Medicine, 3Department of Pathology, 4Cancer

Center, 5Jesse Brown Veterans Affairs (VA) Medical Center, Chicago, IL.

Background: Sickle cell disease (SCD) affects

approximately 100,000 Americans. SCD is a prevalent

and devastating illness caused by a mutation in the in

the -globin gene. Despite the cause of the disease

being understood for decades, the wide spectrum of

disease experienced by patients remains unknown.

The major contributory role of reactive oxygen

species (ROS) in SCD RBCs is supported by our recent

work describing mitochondrial retention in the RBCs

of SCD patients and the SCD mouse model. Oxidative

stress mediated hemolysis and sickling in the RBCs of

SCD patients is possibly exaggerated by lower levels

of antioxidants such as selenium-dependent

glutathione peroxidase 1 (GPX1). GPX1 was first

described as an RBC inhabitant protein and capable of

protecting hemoglobin from ROS and has been

reported to be lower in SCD. Selenium is an essential

component of GPX1 as the amino acid selenocysteine.

The levels and activity of GPX1 are particularly

sensitive to nutritional selenium availability.

Methods: We used the Towns model for the SCD mice

experiments. The mitochondrial content and ROS

levels in RBCs was investigated by flow cytometry.

GPX1 levels were examined by immunoblotting. The

energy profile of circulating RBCs and reticulocytes

was determined by assessing the rate of oxygen

consumption as a marker for mitochondrial

respiration and the extracellular acidification rate, as

a marker for glycolysis using the Seahorse XF

analyzer.

Results: RBCs from HbSS (SCD) mice have significantly

lower GPX1 levels as compared to control HbAA mice

(p<0.003, n=3), indicating that the reduction of GPX1

in SCD may contribute to ROS accumulation. We

further investigated the impact of selenium deficiency

or adequacy in the HbSS mice. Mice were provided

diets either containing 0.02 ppm selenium (deficient)

or 0.1 ppm selenium (adequate) for eight weeks, and

GPX1 levels, mitochondrial retention, oxygen

consumption rate (OCR) and Hb levels were

determined. RBCs of HbSS mice provided a selenium

deficient diet exhibited very low GPX1 levels as

compared to mice maintained on the adequate diet

(p<0.001, n=4). SCD mice in the selenium-deficient

group also exhibited an increase in mitochondria

retaining RBCs (Se deficient: 26%±6.9%, n=3 vs. Se

adequate: 5 % ± 3.5%, n=3, p<0.01), reduced Hb levels

(Se deficient 5.7± 0.17 g/dl, n=3 vs. Se adequate 7.0±

0.83 g/dl, n=4 p<0.05), and an increased OCR.

Conclusions: SCD mice maintained on selenium

deficient diet exhibited reduced GPX1 levels, lower

Hb levels and abnormal erythrocyte energy

metabolism.

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JSCDH-D-19-00044 RENAL MEDULLARY CARCINOMA: THE UNDER-RECOGNIZED AGGRESSIVE SEQUELAE OF SICKLE CELL TRAIT!

Authors: Dianna Hardatt M.D., Rabia Hakim M.D., Isaiah Gonzalez M.D., Revathy Sundaram M.D., Minnie John M.D., Jolanta Kulpa M.D. Affiliation: New York Methodist Hospital Background: Renal Medullary Carcinoma (RMC) is a rare aggressive form of kidney cancer. RMC has a very poor prognosis, and metastasis is seen in up to 95% of the patients at diagnosis or shortly thereafter. Patients tend to be young black males (2:1 male to female predominance) with sickle cell trait. The most common presenting signs and symptoms include hematuria and abdominal or flank pain. The majority of patients have wide spread metastasis at diagnosis which contributes to a poor prognosis. More awareness can lead to earlier diagnosis and even potential lifesaving therapies. Case Presentation: We present a case report of a 20-year-old male with sickle cell trait who presented with abdominal pain and significant weight loss. Positive physical findings included a soft abdomen with left upper quadrant tenderness and tenderness over his L4-L5 region. Differential diagnoses that were being

considered were infection, tuberculosis, collagen vascular disease, sarcoidosis, HIV and malignancy. Extensive imaging eventually revealed a paraspinal mass that was biopsied and was consistent with renal medullary carcinoma. Our patient’s case is unusual in that he did not have a renal mass at the time of diagnosis. Conclusion: Renal Medullary Carcinoma (RMC) is a rare aggressive form of kidney cancer that is predominantly associated with sickle cell trait. Prognosis is poor and the cause is still currently unknown. Sickle cell trait is often considered a benign condition however, it is associated with several complications including splenic infarction, other renal manifestations and even sudden death associated with exercise-induced rhabdomyolysis. Awareness of the clinical spectrum of sickle cell trait can aid in earlier diagnosis of associated morbidities. A high index of suspicion in a patient with sickle trait and weight loss should alert us to the possibility of RMC. This case report emphasizes the fact that sickle cell trait is not a benign disorder and should not be taken lightly.

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JSCDH-D-19-00034 CRIZANLIZUMAB DOSE CONFIRMATION IN PEDIATRIC PATIENTS WITH SICKLE CELL DISEASE: SOLACE-KIDS DESIGN

Authors: Matthew M. Heeney,1 David Rees,

2 Mariane

de Montalembert,3 Isaac Odame,

4 Raquel Merino,

5

Brian Elliott,6 Shankaranand Bodla,

7 Julie Kanter

8

Affiliations: 1Dana-Farber / Boston Children's Cancer

and Blood Disorders Center, Boston, MA, United

States; 2Department of Paediatric Haematology,

King’s College Hospital, King’s College London,

London, United Kingdom; 3Necker Children’s Hospital,

Assistance Publique-Hôpitaux de Paris, Paris, France; 4The Hospital for Sick Children (SickKids), Toronto,

Canada; University of Toronto, Toronto, Canada; 5Novartis Pharma AG, Basel, Switzerland;

6Novartis

Pharmaceuticals Co., East Hanover, NJ, United States; 7Novartis Ireland Ltd, Dublin, Ireland;

8University of

Alabama at Birmingham, Birmingham, AL, United

States

Background: Sickle cell disease (SCD) is the most

common serious single-gene disorder in the world

with complications including acute pain and

acute/chronic organ damage. Episodes of vaso-

occlusion are a hallmark of SCD. P-selectin, an

adhesion molecule expressed primarily on endothelial

cells and platelets, plays a key role in the initiation of

leukocyte rolling along the blood vessel wall,

contributing to multicellular adhesion and

microvascular occlusion. SCD worsens with advancing

age as repeated vascular occlusion results in

cumulative endothelial damage. Crizanlizumab, a

humanized monoclonal antibody, binds to P-selectin,

blocking interaction with its ligands. Crizanlizumab

significantly decreased vaso-occlusive crises (VOCs) vs

placebo and was well-tolerated in SUSTAIN, a phase 2

study in adults with SCD. Here, we report the design

of the first crizanlizumab study in pediatric patients

with SCD.

Methods: Primary objectives of this phase 2,

multicenter, open-label study are to confirm

appropriate dosing and safety of crizanlizumab in

patients >6mo–<18yrs, using sequential, descending

age groups of pediatric SCD patients. Secondary

objectives include number of VOCs and

number/duration of hospitalizations/emergency

room visits. Planned enrollment is ≥100 patients with

confirmed SCD diagnosis (all genotypes), who

experienced ≥1 VOC within the preceding 12mo, in 3

sequential descending age groups: Group 1 (≥26

patients; 12yr–<18yr), Group 2 (≥26 patients; 6yr–

<12yr), and Group 3 (≥8 patients; 2yr–<6yr) and (≥6

patients; 6mo–<2yr). Dose will be confirmed (Part A)

by ≥8 patients in Group 1. If unconfirmed, dose will be

adjusted based on observed

pharmacokinetics/pharmacodynamics, and ≥8

additional patients will be enrolled in Group 1/Part A

to confirm the new dose. After dose confirmation,

Group 1 will be expanded (Part B), with ≥8 patients

enrolled to Group 2 for dose confirmation. This

schema will continue until dose confirmed in Group 3,

which will be expanded for enrollment of an

exploratory group(≥6 patients; 6mo–<24mo). Patients

treated with hydroxyurea/hydroxycarbamide must

have taken it for ≥6mo prior to enrollment and not

plan dose adjustments except for weight changes.

Crizanlizumab (5.0 mg/kg intravenously) will be

administered on weeks 1, 3 and every 4 weeks

thereafter for 2 years.

Results: Trial ongoing (ClinicalTrials.gov:

NCT03474965).

Conclusion: This study will address an unmet need in

pediatric SCD patients by establishing crizanlizumab

pharmacokinetics/pharmacodynamics and confirming

dose in different age groups. Safety will be assessed

as a primary objective. Additionally, the number of

VOCs and number/duration of

hospitalizations/emergency room visits will be

assessed as a secondary objective.

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ABSTRACT SESSION II CLINICAL EPIDEMIOLOGY ORAL

PRESENTATION Presenting: Sunday, June 9, 2019 at 3:30 PM

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JSCDH-D-19-00059 FETAL HEMOGLOBIN AND LEG ULCERS IN ADULTS WITH SICKLE CELL DISEASE

Authors: Seda Tolu, Ugochi Ogu, Andrew Crouch,

Giacomo Vinces ,Caterina Minniti

Affiliation: Albert Einstein Medical Center

Background :Sickle cell disease (SCD) is a

monogenetic inherited disorder with pleomorphic

clinical manifestations. Leg ulcers are a frequent and

debilitating complication of sickle cell disease,

particularly of the SS genotype. Hemoglobin F (Hb F)

concentration is the major genetic modifier of SCD

clinical complications, including leg ulcers, and been

found to be protective in a previous studies.

However, to date, no specific level of hemoglobin F

has been identified that results in prevention and/or

resolution of leg ulcers. Our aim is to determine a

specific threshold of hemoglobin F above which there

is low or no occurrence of leg ulcers in patients with

SCD.

Methods : After obtaining IRB approval, we queried

the Electronic medical records (EMR) of adult SCD

patients in our database at Montefiore Medical

Center, Bronx, New York. EMRs were reviewed in

detail to confirm the documentation of leg ulcers and

laboratory values. Lifetime average hemoglobin F

values were calculated for each patient using all

recorded Hb F values in his or her chart. Patients who

were ever prescribed hydroxyurea (HU) and those

who were not were included in the study.

Results: Out of 804 adult patients with sickle cell

disease, we identified a total of 90 with history of

prior or current leg ulcers, most of which were

chronic in nature. Twenty seven patients were noted

to have a lifetime average Hb F > 8% which included

13 women and 14 men, age range 23 to 72. Four of

these patients were never treated with hydroxyurea

at any point in time. Patient data is displayed in the

table below.

*Never on Hydroxyurea

Discussion: In a modern cohort of post HU patients,

we identified 11 % of SCD patients with leg ulcers, a

higher incidence than what was reported in the

Cooperative Study of Sickle Cell Disease (5%), which

included mostly pediatric patients; but lower than the

Bethesda cohort (~18%), which may have been

enriched for patients with other vasculopathies, such

as high TRV1,2

. A possible explanation is that, as

patients with SCD live longer, the prevalence of leg

ulcers increases, which is evident in our cohort with a

mean age of 37 years and range up to 72 yrs.

Interestingly, we identified 4 patients with

hemoglobin F > 20% who had never been on HU and

developed leg ulcers. Certainly HU could not be

blamed for their occurrence. We conclude that even

very high Hb F levels are not universally protective

against leg ulcers. Intracellular distribution of HbF is

more important than the total HbF, therefore its

effect on hemolysis and in protecting from end organ

damage cannot be predicted solely by the total HbF

level. Patients with hemoglobin F>8 % are still prone

to developing leg ulcers and practitioners should have

high vigilance when taking care of these patients.

Reference 1. Koshy M, Entsuah R, Koranda A, et al. Leg

ulcers in patients with sickle cell disease. Blood 1989;74:1403–1408.

2. Minniti, CP, Taylor JGt Hildesheim M, et al. Laboratory and echocardiography markers in sickle cell patients with leg ulcers. Am J Hematol 2011;86: 705–708.

Age, Sex HbF % Age, Sex HbF % Age, Sex HbF %

64 M 8.3 36 M 11.8 41 M 17.9

35 M 9.3 51 F 12.1 60 M 18.2

38 F 9.5 40 M 12.1 43 F 18.5*

58 F 9.8 58 F 13.7 65 F 20.7

36 F 10.5 23 M 14.9 50 M 20.9*

33 F 10.6 40 F 15.6 62 M 21.5

22 M 10.7 66 F 15.6 72 F 23.7*

41 M 10.8 47 F 16.7 40 M 29.5*

31 M 11.6 42 M 16.8 40 F 31.9

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JSCDH-D-19-00045 CLINICAL TRIAL OF A FETAL GLOBIN INDUCING AGENT WHICH MODULATES REPRESSORS:

BALANCING FACTORS FOR OPTIMAL ACTIVITY

Authors:

1Susan P Perrine,

2Betty S Pace, MD,

3Kevin

Kuo, MD, 4Sylvia T. Singer, MD,

3Rebecca LeRoux, RN,

5Douglas V. Faller, MD,PhD

Affiliations:

1Boston University School of Medicine,

2Augusta University,

3Toronto General Hospital,

University Health Network, 4USCF Menioff Children’s

Hospital at Oakland, 5Phoenicia BioSciences, Inc.

Background: Up-regulation of HbF in a majority of red blood cells is clinically proven to reduce anemia and clinical severity in sickle cell disease (SCD) and beta thalassemia (BT). More than 70 small molecules induce fetal globin gene expression in vitro, through complimentary molecular mechanisms. The timing of addition of inducing agents relative to stage of erythroid differentiation is important for activity. Exposure of erythroid progenitors to most candidates results in high induction only during a period of EPO sensitivity, while exposure in early or late stages of differentiation often has no or minimal effect. A repurposed therapeutic, PB-04, which reduces or abolishes mRNA, protein, and/or binding of multiple repressors (BCL11A, LSD-1, HDAC3) of the fetal globin genes, and promotes appearance of histone activation marks, demonstrates high inducing activity in patients’ erythroid progenitors, in anemic baboons with active erythropoiesis, and in transgenic mice undergoing frequent phlebotomy. PB-04 is reported to not induce HbF in subjects without stress erythropoiesis. The magnitude of fetal globin responses in vitro differs in progenitors of patients

with genomic modifiers associated with variable baseline fetal globin levels. PK parameters of PB-04 in other populations demonstrate brief half-lives, but the drug has been effective for > 40 years in treating an unrelated condition. The design of regimens to optimize these diverse factors may be challenging. Methods: A trial has been designed to investigate human equivalent doses of PB-04 based on intermittent oral administration in anemic baboons, which produces high-level induction (12-30 fold) of fetal globin mRNA and increases F-reticulocytes 3-fold. Three dose-escalating cohorts will be studied initially. If induction is demonstrated, two expansion cohorts in BT intermedia and SCD will be studied. If induction is not observed, dose and schedule will be adjusted based on PK data. Endpoints include PK parameters, HbF, F-reticulocytes/ F-cells, HbF protein/cell, hemolytic assays, hematology. Seven SNPs which affect basal HbF levels, and 2 SNPs which affect cell proliferation, will be assessed. Results: An IND is approved for a PK and preliminary activity study of PB-04 in patients with beta hemoglobinopathies. Conclusions: Intermittent exposure targeting

differentiating erythroid progenitors will be

investigated with an inducing agent which abolishes

BCL11A protein and reduces genomic binding of the

transcriptional repressors LSD-1 and HDAC3. Dose

equivalents and schedule were effective in anemic

baboons and transgenic mice.

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JSCDH-D-19-00055 MICROGLIA-LIKE CELLS DERIVED FROM HEMATOPOIETIC STEM AND PROGENITOR CELLS ARE A MODEL SYSTEM

TO INVESTIGATE CHRONIC PAIN IN SICKLE CELL DISEASE

Authors: Yankai Zhang1, Celeste K. Kanne1, and

Vivien A. Sheehan1

Affiliations: 1. Division of

Hematology/Oncology, Department of

Pediatrics, Baylor College of Medicine, Houston

TX

Background: Patients with sickle cell disease (SCD) often experience severe chronic pain. In chronic pain, microglia are readily activated, stimulating neurons to send a pain signal. Human microglia are difficult to obtain; we proposed to culture induced microglia-like cells (MLC) from human peripheral blood (PB) to develop a model system to investigate chronic pain in sickle cell disease.

Methods: Peripheral blood mononuclear cells

(PBMCs) were obtained from three individuals from

each of the following patient groups: SCD and

chronic pain (SCD CP+, defined as pain most days for

3 months), SCD without chronic pain (SCD CP-), and

normal donors (WT). PBMCs were cultured with

human GM- CSF (10 ng/ml) and human IL-34 (100

ng/ml) to induce peripheral blood derived microglia

(PB-MLC). On day 7 of culture, cells were collected

and morphology analyzed by phase contrast

microscopy, phenotyped by flow cytometry, and

indirect immunofluorescence with anti-CX3CR1,

TMEM119, CD68, Iba1 antibodies. TNF-alpha, IL-

1beta, IL-10 secreted by PB-MLCs were measured

with ELISA. Microglia morphology was evaluated by

quantitative analysis of cell body roundness and

branch length.

Results: When cultured with GM-CSF and IL-34,

PBMCs developed microglial morphology, were

CD11bhigh and CD45low by flow cytometry,

CX3CR1+ and TMEM119+ by fluorescence

microscopy, consistent with microglia. We treated

the PB-MLC with LPS, and found that treated PB-

MLC cells had significantly higher CD68 and Iba1

positivity compared to resting microglia cells,

indicating activation. PB-MLC differed significantly

depending on donor group. SCD CP+ had shorter and

fewer branches than WT; branching from SCD CP-

were intermediate in number and length. Activated

PB-MLC derived from patients with SCD secreted

more inflammatory cytokines than PB-MLC derived

from normal donors, suggesting that donor

characteristics are retained by the PB-MLC. To

evaluate the possibility of using this model system to

screen compounds, we tested MLC cells with the

following drugs: gabapentin, metformin,

piceatannol, and resveratrol. All suppressed the

release of proinflammatory cytokine from LPS-

induced PB-MLC in a dose-dependent manner, and

reversed the deramification of activated PB-MLC

upon LPS stimulation by quantitative analysis of cell

body roundness and branch length with

immunostaning of Iba1, with gabapentin exhibiting

the smallest effect.

Conclusions: We have established the microglia-like

nature of the cultured peripheral blood cells derived

from patients with SCD and normal blood donors.

We propose to use this model system to derive

mechanistic insights into the development of

chronic pain in SCD, and to screen pharmacologic

agents to treat chronic pain.

Acknowledgments: This work was supported by

1K08 DK110448-01 from the National Institute of

Diabetes and Digestive and Kidney Disease

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JSCDH-D-19-00003 WEB-BASED TECHNOLOGY AS A LEARNING TOOL TO IMPROVE DISEASE KNOWLEDGE

IN ADOLESCENT PATIENTS WITH SICKLE CELL DISEASE

Authors: Anjelica Saulsberry, Jason Hodges, Audrey

Cole, Jerlym Porter, Jane Hankins

Affiliation: St. Jude Children’s Research Hospital

Background: Sickle cell disease (SCD) is a chronic,

genetic red blood cell disorder. Advances in SCD

treatment have contributed to an increase in

survivorship of youth with SCD, prompting the need

for “transition readiness” prior to transition into the

adult healthcare system. “Transition readiness”

encompasses disease specific knowledge and self-

management skills and result in improved transition

outcomes. The Sickle Cell Transition E-Learning

Program (S.T.E.P) is a web-based learning tool aimed

at increasing “transition readiness.” For the current

study, we sought to investigate the use and

effectiveness of S.T.E.P. We hypothesize that number

of modules completed will be positively correlated to

improved disease knowledge retention and

confidence in self-management skills.

Methods: The S.T.E.P. program is a public, web-based

6-module tool covering pain, infection, SCD

complications, healthy living, genetics, and self-

advocacy. Self-management confidence was

measured by a self-management skills checklist

(SMSC) modified from the validated Transition

Readiness Assessment Questionnaire. All patients

who participate in the transition program are offered

participation in S.T.E.P. in clinic as a complement to

education sessions. Disease knowledge retention was

measured via an assessment that reflects the entire

educational curriculum provided during adolescent

education visits. Association of S.T.E.P. modules and

disease knowledge retention and self-management

scores were evaluated using Pearson correlations.

Results: Thirty-six African-American adolescents with

SCD between the ages of 12-15 (25 males; 11

females) participated in the S.T.E.P. The number of

modules completed were one (15 participants) two

(10 participants) three (10 participants) and five (one

participant). The average disease knowledge score for

all S.T.E.P. modules was 77 (range of 50-100) for all

participants. A positive correlation (r=0.57) was found

between number of modules completed and final

disease knowledge score (p<0.001). No correlation

was found between number of modules completed

and self-management scores. (Figure 1)

Conclusions: The S.T.E.P. program may serve as a

complement to in-clinic disease knowledge sessions

for increasing disease knowledge retention prior to

transfer to adult care. Further investigation includes

replicating our findings in other SCD patient

populations and conducting a randomized

prospective study to determine the effectiveness of

S.T.E.P. as an intervention to increase disease literacy

in the SCD youth.

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JSCDH-D-19-00058 EXPERIENCES WITH HYDROXYUREA IN AN URBAN ADULT SICKLE CELL DISEASE PATIENT POPULATION

Authors: 1Christopher Bradford, 1Hope Miodownik, 2Gracy Sebastian, NP, 2Merin Thomas, NP, 2Ugochi Ogu, MD, and 2Caterina Minniti, MD

Affiliations: 1Albert Einstein College of Medicine, 2Montefiore Medical Center Background: Hydroxyurea remains the first-line agent for adults with sickle cell disease (SCD), with well- documented improvements in morbidity and mortality. Despite its proven utility, many SCD patients are not prescribed or not taking hydroxyurea. Few studies have evaluated reasons behind this phenomenon among large adult populations. Methods: Adult patients with SCD at a large urban SCD center completed a survey. Data from 224 outpatients were analyzed. Additional information was collected and confirmed using the electronic medical record.

Results: In total, 173 patients (77.2%) have ever been prescribed hydroxyurea. Among these, 65.3% were taking hydroxyurea when surveyed. For those with severe disease genotypes (HbSS or HbS- BetaThal0), 91.0% have ever been prescribed hydroxyurea, with 68.4% taking it when surveyed. Of those with mild disease genotypes (HbSC or HbS-BetaThal+), 42.1% have ever been prescribed hydroxyurea, with 50% taking it when surveyed. Among those patients ever been prescribed hydroxyurea, 17.3% endorsed medication side effects, with fatigue, hair loss, and gastrointestinal distress the most common (each 16.7% of those reporting side effects). Other reasons included dizziness, headache, weight gain, cytopenia, and drug reaction (each 6.7%). Hydroxyurea was discontinued at some point by 35.3% of patients, with 24.6% citing side effects as the cause for discontinuation. Other reasons for discontinuation included

perceived ineffectiveness (19.7%), physician direction (16.4%), reproductive health, ulcer formation, and general dissatisfaction with hydroxyurea (each 8.2%). Conclusions: These results suggest that adult patients with severe SCD genotypes are being prescribed hydroxyurea at high rates, with 91.0% having ever been prescribed, and 68.4% taking it at the time of this study. The largest reason for discontinuation among our patients was medication side effects. Some patients reported well-described side effects (weight gain, cytopenias, hair loss). Others cited side effects that may not be related to hydroxyurea (back pain, depression). Interestingly, 16.4% of patients discontinued hydroxyurea due to perceived ineffectiveness. By identifying variability in reported side effects and reasons for discontinuation, this descriptive study highlights the need for clinicians to clearly communicate benefits and challenges of hydroxyurea use with their patients to further improve rates of prescribing and adherence.

TABLE

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JSCDH-D-19-00031 SUCCESSOR STUDY: BASELINE DEMOGRAPHICS OF THE RETROSPECTIVE, NONINTERVENTIONAL FOLLOW-UP STUDY

IN A SUBSET OF PATIENTS WITH SICKLE CELL PAIN CRISES WHO PREVIOUSLY PARTICIPATED

IN SUSTAIN IN THE UNITED STATES

AUTHORS: Nirmish Shah,1 Ralph Boccia,

2 Walter K.

Kraft,3 Vince Cataldo,

4 Jincy Paulose,

5 Dramane Lainé,

5

Das Purkayastha,5 Abdullah Kutlar

6

AFFILIATIONS: 1Duke University Health System,

Durham, NC; 2Center for Cancer and Blood Disorders,

Bethesda, MD; 3Thomas Jefferson University,

Philadelphia, PA; 4Our Lady of the Lake-Mary Bird

Perkins Cancer Center, Baton Rouge, LA; 5Novartis

Pharmaceuticals Corporation, East Hanover, NJ; 6Sickle Cell Center, Medical College of Georgia,

Augusta University, Augusta, GA

BACKGROUND: SUCCESSOR (SUSTAIN Chart-review of Crizanlizumab to Evaluate Sickle-cell Study One-year Retrospective) reviewed medical records of a subset of patients who completed the SUSTAIN study at US sites to assess subsequent cases of significant pain crisis events and generate real-world data on treatment patterns and health care resource utilization (HCRU) upon completion of crizanlizumab treatment. SUSTAIN was a phase 2, randomized, double-blind, placebo-controlled, 52-week study that compared the effect of crizanlizumab, a P-selectin inhibitor, versus placebo on the frequency of sickle cell pain crises (SCPCs, or vaso-occlusive crises [VOCs] leading to a health care visit) in patients with any genotype of sickle cell disease (SCD). METHODS: SUCCESSOR is a multicenter, retrospective cohort study of a subset of US patients (≥18 years old) who participated in SUSTAIN to evaluate SCD-related outcomes up to 52 weeks following trial completion. SUCCESSOR included the SUSTAIN population who

received at least 12 of the 14 study drug doses, completed a visit at least 14 days after the final dose, and had no major protocol deviations that impacted SUSTAIN efficacy assessments. The post-SUSTAIN study period was from November 2014 to March 2017 and patients’ data were obtained from medical records. Crizanlizumab was not administered in the 52 weeks post-SUSTAIN. Patient consent was obtained prior to data collection if required by local and/or central research ethics review.

RESULTS: In SUCCESSOR, baseline demographic data for 48 patients are reported (15, 18, and 15 patients who were previously randomized in SUSTAIN to receive crizanlizumab 5 mg/kg, crizanlizumab 2.5 mg/kg, and placebo, respectively). The median age was 31.5 years (range 19-65 years) and 69% were female. The majority of patients were Black or African American (96%). One patient had HbSβ

+, 4 had HbSβ

0,

10 had HbSC, 1 had HbS-Lepore disease; all remaining 32 patients had HbSS. The majority of patients live in the Southern US geographic region (63%), followed by the Midwest (18%), Northeast (15%), and West (6%). At 52 weeks post-SUSTAIN, 98% of patients were alive with no bone marrow transplant, no new clinical trial participation, and were not lost to follow-up. No deaths occurred in the 52 weeks post-SUSTAIN. There were high rates of HCRU regardless of the treatment received in SUSTAIN, as more than 60% of patients had at least one hospitalization in the 52 weeks post-SUSTAIN. CONCLUSION: SUCCESSOR is a real-world study generating evidence on VOC rates, treatment patterns, and HCRU in patients post-SUSTAIN.

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ABSTRACT BREAKOUT SESSION II CLINICAL RESEARCH ORAL PRESENTATION

Presenting: Sunday, June 9, 2019 at 3:30 PM

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JSCDH-D-19-00060 A PHASE II RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED MULTI-CENTER STUDY TO ASSESS THE

SAFETY, TOLERABILITY, AND EFFICACY OF RIOCIGUAT IN PATIENTS WITH SICKLE CELL DISEASE (STERIO-SCD)

Authors: Caterina P. Minniti, Kaleab Z. Abebe, Claudia

R. Morris, Victor R. Gordeuk, Mark T. Gladwin,

Gregory J. Kato and the STERIO-SCD Investigators

Affiliations: Department of Medicine, Pittsburgh

Heart, Lung and Blood Vascular Medicine Institute,

and the Center for Clinical Trials & Data Coordination,

University of Pittsburgh School of Medicine,

Pittsburgh, PA; Division of Hematology-Oncology,

Department of Medicine, Montefiore Medical Center,

Bronx, New York; Department of Pediatrics, Division of

Pediatric Emergency Medicine, Emory-Children's

Center for Cystic Fibrosis and Airways Disease

Research , Emory University School of Medicine ,

Atlanta , GA; Division of Hematology and Oncology,

University of Illinois at Chicago, IL.

Background: Systemic hypertension, pulmonary

hypertension and proteinuria are each predictive of

morbidity and mortality in patients with sickle cell

disease (SCD). These complications are associated

with more intense hemolytic anemia and decreased

nitric oxide bioavailability. Riociguat is a soluble

guanyl cyclase stimulator, approved by the FDA to

treat patients with pulmonary arterial hypertension or

chronic thromboembolic pulmonary hypertension.

Methods: STERIO-SCD is an investigator-initiated,

industry-funded Phase 2 multi-center, randomized,

double-blind, placebo-controlled, parallel groups

study aimed to evaluate the safety, tolerability and

the efficacy of riociguat compared with placebo in

patients with SCD. Adult patients are eligible if they

have at least one of the following: Systolic blood

pressure ≥130 mm Hg, urine albumin to creatinine

ratio >300 mg/g, tricuspid regurgitant velocity (TRV)

>2.9 m/sec, NT-proBNP level ≥160 pg/mL, or protein

1+ or higher on urinalysis.

This randomized study involves 12 weeks of

treatment with riociguat pills or placebo pills, and a

follow-up period of 30 days after treatment. The dose

is adjusted every 2 weeks based on systolic blood

pressure, with a goal to escalate from a starting dose

of 1mg TID to 2.5 mg TID. Physical examinations, vital

signs, blood tests and questionnaires are performed

at 2-week intervals during the double-blinded study

treatment. Echocardiogram, urine albumin/creatinine,

six-minute walk distance and the Adult Sickle Cell

Quality of Life Measure (ASCQ-Me) are assessed at

the beginning and end of the treatment phase.

Results: The study is presently open at 11 sites, with

6 more sites in process. Enrollment is underway for a

target of 100 patients completing the treatment.

Additional sites are being sought.

Conclusions: Although many studies are evaluating

efficacy of agents aimed at reducing acute vaso-

occlusive complications of SCD, STERIO-SCD addresses

an unmet need to control the life-limiting, hemolysis-

related chronic vasculopathy associated with death.

Acknowledgment: Bayer provides funding and study

drug for this trial. The University of Pittsburgh is the

study sponsor, data coordinating center and central

pharmacy. STERIO-SCD investigators: Sophie

Lanzkron, Johns Hopkins University; Elizabeth Klings,

Boston University Medical Center; James Ford, UNC

Chapel Hill; Marilyn Telen, Duke University; Payal

Desai, Ohio State University; Laura De Castro,

University of Pittsburgh; Temeia Martin, Medical

University of South Carolina; Wally Smith, Virginia

Commonwealth University; Julie Kanter, University of

Alabama at Birmingham; Ken Ataga, University of

Tennessee. The core team at University of Pittsburgh

includes Carolyn Newkirk, Susan Spillane, Nydia Chien,

Nancy Petro, Yingze Zhang and independent

statistician Seyed Mehdi Nouraie.

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JSCDH-D-19-00053 RESULTS FROM THE DISPLACE CONSORTIUM: PRACTICE PATTERNS ON THE USE OF TRANSCRANIAL DOPPLER

SCREENING FOR RISK OF STROKE IN CHILDREN WITH SICKLE CELL ANEMIA

Authors: 1Shannon Phillips,

1Martina Mueller, PhD,

Alyssa Schlenz, PhD, 1Cathy Melvin, PhD,

1Robert

Adams, MD, MS, Julie Kanter, MD

Affiliations: 1Medical University of South Carolina,

2University of Alabama Birmingham

Background: Stroke is a devastating complication of

sickle cell anemia (SCA). The STOP (Stroke Prevention

Trial in Sickle Cell Anemia) protocol provides

guidelines for stroke screening using transcranial

Doppler ultrasound (TCD) and prevention with chronic

red cell transfusion therapy (CRCT). The DISPLACE

(Dissemination and Implementation Looking at the

Care Environment) study consists of 28 sites across

the US, designed to identify barriers to

implementation of the STOP protocol and test novel

methods for overcoming barriers. The study

presented in this abstract evaluated current TCD and

CRCT measurement and practices at DISPLACE

consortia sites.

Methods: An electronic survey was sent to the

principal investigator (PI) for each site. PIs were

specialty care providers for children with SCA. Items

pertaining to TCD included: screening technique;

screening frequency; follow-up for abnormal,

conditional, and inadequate results; standard value

ranges.

Results: Of the 28 PIs, 53.5% were female, 77.8%

were White, 11.1% were Asian, 7.4% were Black, and

7.4% were Hispanic/Latino. 57.1% of sites use

standard TCD, and 92.9% order TCD annually. To

calculate the time-averaged mean of the maximum

(TAMM) velocities and characterize TCD results,

96.4% of sites use the middle cerebral artery, but sites

also use a variety of other vessels. Table 1 presents

the TAMM ranges used to characterize results. Table

2 presents the actions taken/follow up by TCD result.

Table 1: Minimum and maximum TAMM values (cm/sec) reported by sites with among-site means for results characterized as normal, conditional, and high/abnormal by TCD method compared with the STOP protocol

Normal TCD Low

Normal TCD High

Conditional TCD Low

Conditional TCD High

High/ Abnormal TCD

Low

High/ Abnormal TCD

High

STOP Protocol

(TCD)

169 170 199 200

Standard TCD

Mean 70 170 170 199 200 234

Min 50 169 170 199 200 200

Max 120 179 171 200 201 300

Imaging TCD (TCDi)

Mean 83 163 163 188 190 210

Min 0 149 150 174 180 175

Max 170 170 170 199 200 299

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Conclusions: Nearly all sites order TCD screening

annually, as recommended by guidelines. Variation in

practices pertaining to standard TAMM ranges for

characterizing results, follow up with MRI/MRA, and

initiation of CRCT indicate areas for future study.

Table 2: Action taken or follow-up by TCD result

Action or follow up

(n = 28)

Abnormal/high

% sites (n)

Low Conditional

% sites (n)

High Conditional

% sites (n)

Inadequate

% sites (n)

Initiate HU if not currently on 7.1 (2) 57.1 (16) 67.9 (19) 7.1 (2)

Start CRCT 85.7 (24) 0 3.6 (1) 0

No change 0 0 3.6 (1) 3.6 (1)

Initiate HU and CRCT 3.6 (1) 0 0 0

Obtain MRI/MRA 64.3 (18) 32.3 (11) 46.4 (13) 57.1 (16)

Repeat TCD prior to change 28.6 (8) 71.4 (20) 96.4 (27) 60.7 (17)

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JSCDH-D-19-00036 DEVELOPMENT AND EVALUATION OF A SICKLE CELL DISEASE SEVERITY INDEX TO

VALIDATE CLINICAL ADHESION BIOMARKERS

Authors: Jennell White

1,2,4, Ke Liu

4, Xiufeng Gao

4,

Michael U. Callaghan2,5

, Patrick Hines3,4,6

Affiliations: Department of Pharmacology1, Carman

and Ann Adams Department of Pediatrics2,

Department of Physiology3, Wayne State University

School of Medicine, Detroit, MI; Functional Fluidics,

Detroit, MI4; Division of Hematology

5, Division of

Critical Care Medicine6, Children’s Hospital of

Michigan, Detroit, MI

Sickle cell disease (SCD) is a complex multisystem

organ condition characterized by vaso-occlusive

events and significant phenotypic variability. There is

no universally accepted system to objectively define

sickle cell disease (SCD) severity, which has hindered

attempts to validate the clinical utility of SCD

biomarkers. We developed an objective clinical SCD

severity index (SCDSI) that reflects an individual’s

cumulative life-time burden of SCD-related vaso-

occlusive pathology. An SCDSI was established by

quantifying the total number of objectively

documentable vaso-occlusive end-organ events,

including acute chest syndrome, stroke, priapism,

splenic sequestration, hepatic sequestration, and

cholelithiasis indexed over the total years of life. Each

objectively documentable “event” is given equal

weight in the scoring system for simplicity. These

events were selected because they could be

objectively verified via retrospective review of

medical records within a typical healthcare system or

practice. We evaluated the SCDSI in 35 subjects with

HbSS disease who were enrolled in a longitudinal SCD

study that validated real-time clinical status via a

previously described electronic patient reported

outcome tool (ePRO)1. Daily patient input validated

the patient -reported steady state of each individual

patient over 6 months. We developed a microfluidic,

flow-based adhesion bioassay to measure erythrocyte

adhesive properties (previously described2) in a CLIA

lab environment. Clinical adhesion biomarkers were

obtained every 3 weeks at the patient’s home during

baseline clinical status validated by daily self-report.

Baseline adhesion indices showed a strong positive

correlation with the SCDSI of the study subjects

(r=0.585, p<0.0011), validating that the cumulative

lifetime burden of vaso-occlusive pathology is

reflected in the erythrocyte adhesive index during the

subjects baseline clinical state. The goal of SCD-

modifying therapy is to ultimately reduce the vaso-

occlusive pathology by improving the health and

survival of the sickle erythrocytes. The results of this

study suggest that erythrocyte health, as assessed by

a standardized clinical adhesion assay, may be a

surrogate for clinical disease severity. The SCDSI

provides a simple and accessible scoring system for

clinicians to quantify historical disease burden for

individuals with SCD. Further studies are needed to

validate the utility of the SCDSI in assessing the

clinical utility of SCD-specific biomarkers in clinical

practice. A prospective study is underway to

determine the predictive value of the SCDSI for

prospective vaso-occlusive complications in this SCD

population.

1. Callaghan MU, Hines PC, Pittman DD, et al. Elipsis: A Longitudinal Study of Electronic Patient-Reported Outcomes, Actigraphy and Biomarkers to Identify and Assess at-Home Vaso-Occlusive Crises in Adults and Adolescents with Sickle Cell Disease. American Society of Hematology Annual Meeting. Atlanta, GA: The American Society of Hematology; 2017:973. 2. White J, Lancelot M, Sarnaik S, Hines P. Increased erythrocyte adhesion to VCAM-1 during pulsatile flow: Application of a microfluidic flow adhesion bioassay. Clin Hemorheol Microcirc 2014.

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JSCDH-D-19-00061 SICKLE CELL TRAIT PRESENTING AS SICKLE CELL DISEASE: A CASE REPORT

Authors: Erin Goode DO, Donna Boruchov MD, Ching Lau MD Affiliations: University of Connecticut, Connecticut Children’s Medical Center Background: Sickle cell disease is a hemolytic anemia with vaso-occlusive complications, including pain, tissue ischemia, splenic infarct, and recurrent infections. It occurs secondary to two abnormal hemoglobin beta globin chains; the glutamic acid is switched with valine at the sixth position. In contrast, children with sickle cell trait have one abnormal allele present, with both hemoglobins A and S. This is clinically protective and explains why these individuals are usually asymptomatic. An eight year old male, diagnosed with sickle cell trait on newborn screen, was admitted for worsening right calf pain. He was diagnosed with acute osteomyelitis of right distal femur, with myositis, requiring surgical intervention and antibiotics. His hospitalization was then complicated with avascular necrosis of his right femur and stuttering priapism lasting six days. Objective: To expand focus beyond a patient’s newborn screen results, and to understand the complete clinical picture, when caring for a child with sickle cell trait. Understanding the possible sequelae of children with rare hemoglobinopathies and the appropriate evaluation for diagnosis. Design/Methods: Work up included hemoglobin electrophoresis, DNA sequencing, and mass spectrometry. Thorough past medical history assessment and chart review completed. Family history investigated in detail and hemoglobin evaluation of both parents performed. Results: Chart review showed failure to thrive, with documented weight of 18.2 kg (1st percentile) and height 107 cm (3rd percentile) at seven years old. Recurrent bone and abdominal pain observed since two years of age. Starting at five years old, electrophoresis was performed multiple times, which revealed both hemoglobin A and S.

On admission, his hemoglobin was 8.2, with 6.5 percent reticulocytes. Hemoglobin fractionation showed Hb S 29.8%, Hb A and Hb Quebec-Chori 61.7%, Hb A2 2.6%, and Hb F 5.8%. This abnormal hemoglobin was confirmed with DNA sequencing and mass spectrometry, which revealed his abnormal beta globin chain. Positive sickle solubility test. Conclusion: This patient’s newborn screen and initial hemoglobin evaluations did not confirm sickle cell disease, although he experienced complications expected with sickle cell disease rather than trait. After many hospitalizations, this patient’s diagnosis was confirmed on electrophoresis revealing heterozygous for Hb S and Hb Quebec-Chori. This hemoglobin variant is due to a substitution of the 87 position on the beta chain, from Thr to Ile, indistinguishable from hemoglobin A on electrophoresis. This hemoglobin variant has only been described two times previously and can result in severe sickle cell disease, making it important to detect early, before the patient experiences complications. REFERENCES 1. Rees, DC, William, TN & Gladwin, MT. Sickle-cell disease. Lancet 2010: 376: 2018-2031. 2. Pauling, L., Itano, H., et al. Sickle cell anemia, a molecular disease. Science. November 1949; 110: 543-548. 3. Edward, R., Griffiths, P. et al. Compound heterozygotes and beta-thalassemia: Top down mass spectrometry for detection of hemoglobinopathies. Proteomics, 2014: 14: 1232-1238. 4. Monplaiser, N., Merault, G. et al. Hemoglobin S Antilles: A variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes. Proc Natl Acad Scin USA 1986; 83: 9363-9367. 5. Witkowska, H., Lubin, B., et al. Sickle cell disease in a patient with sickle cell trait and compound heterozygostiy for hemoglobin S and hemoglobin Quebec-Chori. N Engl J Med 1991; 325 (16): 1150-1154. 6. Tubman, V., Bennett, C., et al. Sickle cell disease caused by Hb S/Quebec-CHORI treatment with hydroxyurea and response. Pediatric Blood & Cancer, August 2007; 49 (2): 207-210.

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JSCDH-D-19-00021 FEASIBILITY AND QUALITY VALIDATION OF A MOBILE APPLICATION FOR ENHANCING

ADHERENCE TO OPIOIDS IN SICKLE CELL DISEASE

Authors: Daniel Sop1, 2 *

, Wally Smith1, Azhar Rafiq

3,

Abdulkhaliq Alsalman1, Donna McClish

4, Shirley

Johnson1, Thokozeni Lipato

1, Ding-Yu Fei

2

Affiliations: 1

Department of General Internal

Medicine, 2Department of Biomedical Engineering,

3Department of Surgery, and

4Deptment of

Biostatistics, Virginia Commonwealth University,

Richmond, VA 23298, USA

Introduction: American health literacy is poor,

thereby compromising medication adherence, patient

safety, and important health outcomes. Prescription

opioid nonadherence, specifically opioid misuse, has

likely contributed to the prescription opioid epidemic

and opioid-related morality in the US. Popular

methods to measure and control opioid adherence

have limitations, but mHealth, specifically

smartphone applications, offer a potentially useful

technology for this purpose.

Methods: We conducted Phase IV feasibility testing of

the OpPill application, a mobile monitoring and

reporting system intended to enhance health literacy

and adherence by collecting data and providing

systematic feedback on pain and opioid use. We

asked patients with Sickle Cell Disease (SCD) to

review, test, and evaluate the OpPill application, all at

one sitting. Immediately after OpPill review and use,

patients completed the Mobile Applications Rating

Scale (MARS), a validated tool for assessing the

quality of health mobile apps. The MARS contains 4

scales (range of each scale= 0-4) that rate

engagement, functionality, aesthetics, and

information quality. It also asks items that rate

subjective quality, relevance and overall application

impact.

Results: Patients (n=28) all had one of various SCD

genotypes; were ages 19 to 59 yrs (mean 36.56); 53.6

% were female, and; 39.3% had completed some

college. Patients rated the OpPill application highly

on four scales: Engagement, 3.93 ± 0.73;

Functionality, 4.54 ± 0.66; Aesthetics, 3.92 ± 0.81;

Information, 3.91 ± 0.87. The majority of patients

found the application to be relevant for their care.

Ninety-six percent of patients reported the

information within the app was complete, while 4%

estimated the information to be minimal or

overwhelming. Patients (91.7%) overwhelmingly

reported that the quality of information as it

pertained to SCD patients was relevant; only 8.3%

found the application to be poorly relevant to SCD.

Similarly, patients (91.7%) overwhelmingly rated both

the application’s performance and ease of use

positively. The large majority of participants (85.7%)

found the application to be interesting to use, while

74% found it entertaining. All users found the

application’s navigation to be logical and accurate

with consistent and intuitive gestural design.

Conclusion: We conclude that surveyed SCD patients,

using a validated rating tool, rated the OpPill

application, specifically targeted to monitor opioid

use and pain and opioid behavior in patients with

Chronic Non-Cancer Pain, as feasible and easy to use

Keywords: Medical Apps, Pain management, Opioids,

Chronic Condition, Sickle Cell Disease, mHealth

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JSCDH-D-19-00063 CARDIAC INJURY IN SICKLE CELL DISEASE

Authors: Kiranveer Kaur, MD1, Huang Ying, MS

2, Eric

Kraut, MD2, Subha Raman, MD

3, Payal Desai, MD

2

Affiliations: 1

Division of Medical Oncology; 2Division of

Hematology; and 3Division of Cardiovascular

Medicine, The Ohio State University, Columbus, OH

Background: Previous study at our institution has shown that 3/22(13%) patients with clinically stable sickle cell disease(SCD) had impaired myocardial perfusion reserve but no epicardial coronary artery disease. The prevalence of this microvascular disease and utility of cardiac troponin in predicting such changes has not been clearly defined. In this study, we evaluated the prevalence of myocardial ischemic injury in SCD. We also examined the sensitivity and specificity of troponin levels to predict microvascular ischemic injury in patients with SCD.

Methods: We conducted a retrospective chart review of patients with SCD seen at OSU Wexner Medical Center from July 2005 to July 2015 to identify patients with troponin-I elevation (normal <0.11 ng/mL) and/or myocardial ischemic changes on cardiac MRI. Clinical and laboratory values related to these events were analyzed. Abnormal cardiac MRI was characterized by impaired subendocardial or myocardial perfusion, myocardial fibrosis or edema, and cardiomyopathy. Fisher’s exact test and Wilcoxon rank sum test were used for data analysis for categorical and continuous variables respectively.

Results: Sixty-nine (51% male; genotype Hb SS 75%, SC 16%, and Sβ-thal 9%) of 373 SCD patients had either abnormal troponin and/or had cardiac MRI done. Median age was 34 years (range 19-67 years). Of 230 patients who had troponin-I measured over this period, 18.2% (n=42) had elevated troponin. 26 of 47 patients with cardiac MRI showed abnormalities described above concerning for microvascular disease and myocardial injury. We identified 22 patients with troponin measurement within 30 days before cardiac MRI. Elevated troponin levels predicted MRI abnormalities with sensitivity of 71% (CI 42-92%) and specificity of 65% (CI 24-91%). The degree of troponin elevation did not correlate with the MRI changes. At the time of data review, 31%(n=8) patients with abnormal MRIs and 52%(n=22) patients with elevated troponin levels were deceased.

Conclusion: Over 10-year period, prevalence of cardiac injury as measured by elevated troponin was 18.2%(42/230) in SCD patients with atypical chest pain. The incidence of microvascular cardiac disease was at least 7% as diagnosed by cardiac MRI. In this small cohort, troponin elevation was neither highly sensitive nor highly specific for microvascular cardiac disease. As cardiac complications are known to be related to high frequency of deaths in SCD, there must be high index of suspicion for cardiac disease in patients with SCD and chest pain. More data is needed to accurately predict associated mortality and identify interventions to modify the outcome.

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JSCDH-D-19-00026 MODELING INPATIENT OPIOID CONSUMPTION PATTERNS IN TEENAGERS WITH SICKLE CELL DISEASE

Authors: Sarah Pourakbar, MS41, Oluwaseum Olaiya,

DO2, Gerald Woods, MD

2, Colleen Reisz, MD

1

Affiliations: 1

University of Missouri Kansas City School

of Medicine; Kansas City, Missouri 2Children’s Mercy Hospital Kansas City; Kansas City,

Missouri

Background: The opioid epidemic continues to be a

significant public health issue and involves both

legitimate use and illicit drug access. Standard

management of patients with sickle cell disease (SCD)

includes treatment with opioids amongst other

strategies. SCD patients have disease-related

obstacles to achieving developmental milestones, and

therefore we theorize that these patients are at a

higher risk of accelerated trajectories of opioid use.

While only 5% of SCD patients account for the

majority of inpatient hospitalizations for painful

episodes, we sought to develop visual and

mathematical models of inpatient opioid

consumption between the ages of 12-18, to see if

patterns existed that would assist the clinician, the

patient, and the patient’s family in forecasting the

amount and duration of opioid use. We hypothesize

that clear visualization of past patterns in acceleration

and remittance of opioid consumption in real time

could trigger clinical decision support for issues that

may contribute to tolerance and addiction.

Methods: A longitudinal study using data from Cerner

Health Facts, a database that captures and stores de-

identified, longitudinal electronic health record data,

and then aggregates and organizes the data into

consumable data sets to facilitate analysis. Opioid

amount and number of doses per year, along with

gender, age, and region of the country were extracted

from the database, using ICD 9 and 10 diagnosis codes

on patients with SCD between the ages of 12-18. Data

was extracted on 451 individual patients across 862

encounters. Simple linear regressions were conducted

to examine the relationship between both age and

dose, and age and amount.

Results: Of the 451 individual patient encounters, 36

patients with SCD were identified as high utilizers

with greater than 5 hospital encounters. Linear

regressions conducted on the relationship between

age and dose yielded steady increases in the mean

dose administered across these 36 patients as age

increased. When taking each of these individual SCD

patients with greater than 5 hospital admissions, each

individual patient had cumulative dose of opioids

administered per year graphed at each age between

the ages of 12-18.

Conclusions: Attempts to manage opioid

consumption in chronic disease will require

comprehensive interventions that can be mobilized at

the time sharp changes in opioid consumption occur.

Graphing opioid consumption across a set age range

allows visual identification of opioid trajectory.

Practitioners could utilize this tool to isolate trends,

recognize previous prescribing patterns and highlight

deviations in consumption between painful episodes

and baseline that forecast tolerance and addiction.

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JSCDH-D-19-00019 A PROSPECTIVE PHASE II, OPEN-LABEL, SINGLE-ARM, MULTICENTER STUDY TO ASSESS THE EFFICACY AND SAFETY

OF SEG101 (CRIZANLIZUMAB) IN SICKLE CELL DISEASE PATIENTS WITH PRIAPISM (SPARTAN)

Authors: Fuad El-Rassi,1 Deepika Darbari,

2 Arthur

Burnett,3 Jincy Paulose,

4 Dramane Lainé,

4 Das

Purkayastha,4 Greg Kato

5

Affiliations: 1

Department of Hematology and Medical

Oncology, Winship Cancer Institute of Emory

University, Atlanta, GA, United States; 2Center for

Cancer and Blood Disorders, Children’s National

Medical Center, Washington, DC, United States; 3The

James Buchanan Brady Urological Institute and

Department of Urology, The Johns Hopkins School of

Medicine, Baltimore, MD, United States; 4Novartis

Pharmaceuticals Co., East Hanover, NJ; 5Heart, Lung,

Blood and Vascular Medicine Institute, University of

Pittsburgh School of Medicine, Pittsburgh, PA, United

States

Background: Sickle cell disease (SCD) is the most

common single-gene disorder in African Americans

and can lead to complications, including acute pain

and acute/chronic organ damage. Approximately 40%

of men with SCD experience priapism, a clinical

disorder characterized by prolonged, painful penile

erection in the absence of sexual stimulation. Vaso-

occlusion-induced ischemia is generally thought to

account for SCD-associated priapism. Crizanlizumab, a

humanized monoclonal antibody that binds P-selectin

and blocks interaction with its ligands (including

leukocyte PSGL-1). The antibody significantly

decreased vaso-occlusive crises (VOCs) leading to

healthcare visit vs placebo, and was well tolerated in

SUSTAIN, a phase 2 study in adults with SCD. This

study aims to evaluate the clinical efficacy of

intravenous (IV) crizanlizumab 5 mg/kg in reducing

priapic events in patients with SCD and a history of

priapism.

Methods: This is a Phase 2, multicenter, open-label,

single arm study of crizanlizumab in male patients

aged ≥16 years with SCD-related priapism. The study

will consist of 14 weeks prescreening, 12 weeks

screening, and 52 weeks of treatment. The primary

endpoint is percent reduction from baseline of priapic

events frequency (unwanted/painful erection lasting

>60 minutes) by 26 weeks. Priapic events will be self-

reported via an electronic reporting system.

Secondary endpoints include: safety as well as the

following outcomes at 26 and 52 weeks: rate of

priapic events, percent reduction in ≥4-hour erections

requiring an ER visit, rate of VOC at 26 and 52 weeks,

and rate of complicated crises. Approximately 56

patients are planned to be enrolled in the study. The

baseline period will consist of a 14 week prescreening

period and a 12 week screening period. Eligible

patients must have ≥4 events during prescreening, ≥3

during screening with 1 event occurring within 4

weeks prior to first treatment. Patients will be treated

with IV crizanlizumab 5 mg/kg on the first day of

Week 1, Week 3 (loading dose), Week 7, and then

every 4 weeks until final treatment at Week 51.

Primary analysis will be conducted after patients

receive 26 weeks of treatment. Mandatory safety

follow-ups will be conducted until 15 weeks after last

dose.

Results: Trial ongoing

Conclusions: This study aims to address the unmet

treatment need in male patients >16 years old with

SCD-related priapism.

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JSCDH-D-19-00029 IMPACT OF PHYSICIAN EDUCATION ON TIMELY INTRAVENOUS OPIOID DELIVERY AND FLUID BOLUS USE

FOR ACUTE PAIN MANAGEMENT IN CHILDREN WITH SICKLE CELL DISEASE IN THE PEDIATRIC EMERGENCY DEPARTMENT

Authors: 1Kirshma Khemani, MD;

1Joseph Malicki;

Shabnam Jain, MD; 1Michael Kelleman;

1Courtney

McCracken PhD; 2Lakshmanan Krishnamurti, MD;

2Claudia R. Morris, MD

Affiliations: 1Emory University School of

Medicine, 2Children’s Health Care of Atlanta

Background: Pain is the leading cause of pediatric emergency department (PED) visits for children with sickle cell disease (SCD). NHLBI recommends rapid evaluation and treatment of moderate-severe vaso-occlusive pain episodes (VOE) in the acute care setting, including parenteral opioids within 30min of triage or 60min of arrival, frequent pain reassessments, and re-dosing of opioids within 30min. The guidelines also discourage intravenous fluid (IVF) boluses in euvolemic patients with VOE, recommending IV hydration at no more than maintenance rate to avoid over-hydration in patients unable to drink fluids. PED adherence to NHLBI guidelines is variable. We therefore designed a Maintenance of Certification (MOC, part-4) quality improvement (QI) project for physicians in an effort to improve care.

Methods: Thirty physicians enrolled in a MOC/QI initiative where they attended two educational interventions and received monthly performance feedback reports. A retrospective analysis of prospectively collected data from electronic medical records for SCD patients seen by these providers was performed for pre-intervention (7/2017–3/2018) and post-intervention (4/2018–12/2018) phase to evaluate the impact of the intervention. Outcome measures, derived from the 2014 NHLBI VOE guidelines, included: IV opioid administration within 60 minutes of ED arrival, pain reassessment between 10–30 minutes after administration of IV opioids, IV opioid re-administration between 15–60 minutes after administration of first IV opioid, and IV fluid bolus use. 72-hour-return rate was the balancing measure. As a QI project, the data was analyzed as a function of time utilizing run charts.

Results: A total of 354 patient visits in the pre-

intervention and 269 patient visits in the post- intervention phase met inclusion criteria. The proportion of patients receiving an IV opioid within 60 minutes of arrival increased significantly from 26% to 36%, p=0.004 with a significant decrease in median time to administration from 87 minutes to 75 minutes, p=0.007. Improvement in pain reassessment after opioid administration was noted. The proportion of patients receiving an IV fluid bolus decreased from 40% to 11%, p<0.001 (Fig1). No change in the 72-hour-return rate was observed.

Conclusions: Implementation of an educational intervention combined with performance-based feedback reports led to significant improvements in the treatment of VOE, although further efforts are needed to reach goals outlined in the 2014 NHLBI guidelines. The progress made suggests that education combined with performance feedback may be a viable option for future QI initiatives to improve adherence to NHLBI guidelines and improve PED-based care for acute pain in SCD.

FIGURE 1

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JSCDH-D-19-00006 EVALUATION OF THE CLASS I HISTONE DEACETYLASE (HDAC) INHIBITOR CT-101 ON FETAL HEMOGLOBIN (HBF)

EXPRESSION IN SICKLE PROGENITORS AND TRANSGENIC MICE Authors: Biaoru Li, PhD, Betty Pace, MD, Jose Sangerman, PhD, Mayuko Takezaki, MS, Michael Boosalis, PhD, Clifford Hendrick, BS, Louis Junker, PhD, Vy Le, PhD, Anil Shelke, PhD, Robert Williams PhD, Susan Perrine MD

Affiliations: Department of Pediatrics, Augusta , University, Augusta, GA Boston University School of Medicine, Boston, MA, Cetya Therapeutics, Fort Collins, CO

Background. Up-regulation of HbF is a clinically proven strategy for mitigating the clinical severity and disease phenotype of sickle cell disease patients. HDAC inhibitors including butyrate, phenylbutyrate, and dimethyl butyrate have shown activity in clinical trials. We explored whether the HDAC inhibitor CT-101 would increase HbF over adequately broad concentrations to be useful for therapy, without significantly inhibiting erythroid cell growth in sickle erythroid progenitors and in the β-YAC transgenic mouse model. Drug candidates that induce HbF in these mice have demonstrated subsequent in vivo γ-globin gene activation in human trials.

Methods. CT-101 (100-200 nM) was evaluated in erythroid progenitors generated in vitro from peripheral blood mononuclear cells isolated from 6 patients with sickle cell anemia (HbSS or

HbSβ0thalassemia). In vivo studies were conducted in β-YAC mice established with the 248 Kb human β-

globin locus, which display normal γ-globin to β-globin switching during development. β-YAC mice were treated with IP CT-101 (5 mg/kg/dose) or vehicle for 3 days/week and hydroxyurea (HU, 100 mg/kg/dose), 5 days/week. F-cell proportions were assayed using anti-γ-globin FITC antibody and HbF/cell quantified using mean fluorescence intensity (MFI) by flow cytometry.

Results. In sickle progenitors, CT-101 and HU increased F-cells by 30% and 20% respectively above control cultures from the same subject (p<0.001). HbF protein/cell by MFI increased by up to 1.6-fold above vehicle controls. Additive effects were observed with combined CT-101 (100 to 200nM) and HU (75μM) (p< 0.001). Erythroid progenitor proliferation did not decrease significantly with CT-101. Treatment with CT-101 in β-YAC mice increased F-cells by 2.5-fold compared to baseline (p=0.034) and by 1.6-fold with HU (p=0.352). HbF protein by MFI increased1.8-fold, (p=0.025) with CT-101 versus 0.9-fold (p=0.694) with HU.

Conclusions. The HDAC inhibitor CT-101 demonstrates HbF inducing activity in β-YAC mice and additively induces HbF expression in sickle erythroid progenitors with HU. These findings suggest that CT-101 may be useful in patients who have low or partial responses to HU and merits further investigation as a HbF-inducing agent.

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JSCDH-D-19-00056

RISK FACTORS FOR IDENTIFYING CARDIOVASCULAR MORBIDITIES IN SICKLE CELL DISEASE PATIENTS

Authors: Isaiah Gonzalez, Dianna Hardatt, Gulnigor

Ganieva, Manoj Chhabra, Yang Liu, Pramod Narula,

Jolanta Kulpa, Revathy Sundaram

Affiliation: New York Methodist Hospital

Background: Pulmonary hypertension and cardiac

dysfunction are complications of sickle cell disease

(SCD) that develop independently but have an

important additive impact on morbidity, mortality,

and quality of life. Although there are numerous

studies in the adult population, studies in the

pediatric population are less common. Likewise,

many studies examine single variables instead of

looking at multiple variables to identify patterns for

further analysis. Survival in SCD patients has

improved with scientific advances in care and

management. Cardiac and renal complications as

well as vaso-occlusive crisis are being addressed.

Aim: The goal of our study was to evaluate the

correlation between BMI, age, hemoglobin, and O2

saturation and parameters of cardiac dysfunction

such as left ventricular abnormalities and pulmonary

hypertension in SCD patients.

Methods: A retrospective chart review was

performed of patients 2-20 years of age with a

diagnosis of SCD who had routine hematology and

cardiology outpatient visits from January 2017 to

March 2019. Patients with HbSS, HbSC, and Hb S-

Beta Thal were included in the study. Complete data

was available for 47 patients. During cardiology visits

patients had echocardiograms performed. BMI and

O2 saturation were documented. The parameters

reviewed in this study were O2 saturation, BMI, BMI

percentile, age, hemoglobin level, and ECHO findings

including left ventricular dimensions and tricuspid jet

velocity.

Results: A total of 47 pediatric patients with sickle

cell disease were included in the study. Age showed

a strong positive correlation LV dimension findings

(LVPWd 0.65, LVIDd 0.66, IVSd 0.70) and tricuspid jet

velocity (0.35). BMI had a positive correlation with

LV dimension findings (LVPWd 0.57, LVIDd 0.66, IVSd

0.65), however a weak association with tricuspid jet

velocity (-0.06). O2 saturation correlated negatively

with echocardiogram variables, however after

controlling for other variables was no longer

significant. Hemoglobin does not correlate as a

univariate, but appears to be significant in the model

after controlling for other variables.

Conclusion: This study is intended to be a

continuation of previous research that included EKG

findings and compared HbSS and HbSC. In this study

age and BMI had a strong correlation with increased

LV dimensions, however BMI did not correlate with

tricuspid jet velocity. O2 saturation did not correlate

with ECHO findings. In the model, as hemoglobin

decreases echocardiogram findings of IVSd

increases. We plan to continue our study to evaluate

other parameters of echocardiogram, hydroxyurea

use, and acute chest syndrome as predictors of

cardiovascular morbidity.

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JSCDH-D-19-00054 AP-1 TRANSCRIPTION FACTOR DYSREGULATION MAY CONTRIBUTE TO B CELL DYSFUNCTION AND REDUCED

EFFICACY OF PNEUMOCOCCAL VACCINATION WITH PREVNAR-13 IN SICKLE CELL DISEASE MICE

Authors: Steven M. Szczepanek, Tyler Gavitt, B.Sc.

Affiliation: University of Connecticut

Background: Patients with Sickle Cell Disease (SCD) are at increased risk of infection with encapsulated bacterial species including Streptococcus pneumoniae. Repeated microvascular infarction leads to extensive damage to the spleen, a major immunological site for B lymphocyte development, and functional asplenia in SCD patients is thought to contribute to B cell dysfunction. Prior work in mouse models of SCD has indicated that mice vaccinated with Prevnar-13, mount robust early immune responses to the vaccine, but are incapable of maintaining antibody titers over long time periods. RNA-seq data from vaccinated and unvaccinated SCD and WT murine B cells has identified a dysregulation of AP-1-family transcription factors (TFs) c-Jun and c-Fos, two factors implicated in cell division, differentiation, and suppression of apoptosis. The importance of these three activities in memory B cell formation marked these factors as important candidates for further investigation.

Methods: To establish the role of these AP-1 TFs in B cell responses to vaccination, 8-week-old female C57Bl/6 mice were vaccinated with Prevnar-13 with or without administration of SP600125, a chemical inhibitor of the Jun N-terminal kinase which regulates c-Fos and c-Jun activity. Mice were vaccinated on days 0 and 21, with inhibitor given D-1, D0, and D1 of each vaccine bolus. 5 weeks post-boost, mice were challenged IP with 1x10

5 CFU S.

pneumoniae strain A66.1 (Serotype 3, covered by Prevnar-13). An additional unvaccinated group was used as an infection control. Mice were examined for clinical signs, weight loss, and mortality over a 21-day period post infection.

Results: All unvaccinated mice (5/5) succumbed to challenge by 3 d.p.i. Vaccinated but uninhibited mice showed 0% mortality (0/5). In comparison, vaccinated and inhibited mice showed 20% mortality (1/5). Due to concerns of insufficient power, the study was repeated with higher numbers of mice. In a follow-up experiment utilizing the same experimental conditions with larger group sizes, vaccinated but uninhibited mice once again showed

0% mortality, but mortality in the inhibited group dropped to 6% (1/15), for a cumulative mortality between the 2 studies of 10% in mice receiving SP600125.

Conclusions: This data suggests that inhibition of AP-1 TFs in a vaccination and challenge model of pneumococcal infection impairs immune responses to bacterial challenge. Dysregulation of these TFs may partially explain B cell dysfunction in SCD, but further investigation is necessary to solidify this model and thoroughly uncover the roles of AP-1 in B cell function in the context of pneumococcal vaccines.

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POSTERS Presenting: Sunday, June 9, 2019 at 5:15 PM

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JSCDH-D-19-00001 PAMIDRONATE USE IN SICKLE CELL DISEASE

Authors: Loretta Parker, Jennifer Keates-Baleeiro,

Wendell Moses, Joni Evans

Affiliations: University of Tennessee College of

Medicine Chattanooga, Pediatric Orthopaedics-

Children’s Hospital at Erlanger

Introduction: Avascular necrosis (AVN) of the femur is

a serious complication from sickle cell disease (SCD),

defined as lack of blood supply leading to death of

bone and collapse.1 Scant literature is available on

non-invasive treatment for AVN due to SCD in

children. Methods: Patient inclusion criteria: HbSS or

HbSS B0Thalassemia, femoral head AVN, 0-18 years,

perfusion of the lateral corner, and Pamidronate

therapy. Each cycle consisted of labs and 3

consecutive days of Pamidronate, continuing until

improvement or a maximum of 2 years. Results: Four

patients were diagnosed with AVN and treated

successfully with Pamidronate. Conclusion:

Pamidronate prevents resorption of bone, with

effects on calcium homeostasis. Our case series

demonstrates success of Pamidronate in SCD and our

hope is to inspire more in-depth research.

Introduction: Avascular necrosis (AVN), or

osteonecrosis, is a terrible complication that can

result from sickle cell disease (SCD). Avascular

necrosis occurs due to congestion and increase in

sickling in the vasculature, resulting in death of bone

and collapse.1 Along with pain, there can be

significant destruction. Pamidronate is effective in

treatment of AVN only if there is evidence on MRI of

healthy bone in the lateral corner. Our aim was to

evaluate how to improve non-invasive treatment

options. There is little evidence with using non-

operative treatments for AVN due to SCD in children.

This case series demonstrates the success of

Pamidronate as a conservative treatment option for

AVN in children with SCD.

Methods

Patients: From our comprehensive sickle cell

population of 120 patients, four developed AVN of the

femoral head. All patients were boys and were

included in the study if they: 1) had HbSS (3 patients)

or HbSS B0

Thalassemia (1 patient), 2) were diagnosed

with AVN on MRI (which showed decreased uptake in

contrast), 3) had preserved perfusion of the lateral

corner of the femoral head, 4) were aged 0-18 years,

and 5) were treated with Pamidronate. Exclusion

criteria included: 1) sickle cell trait, 2) sickle cell SC

disease, 3) those who did not develop AVN, or 4) were

not treated with Pamidronate.

Diagnosis: Imaging was performed during pre-

treatment to establish AVN, as well as post-treatment

to evaluate results of Pamidronate. Imaging

modalities were an x-ray or an MRI, either alone or for

confirmation.

Treatment: After establishing a diagnosis of AVN,

patients were evaluated by orthopedics to determine

whether Pamidronate would be appropriate.

Candidates for Pamidronate were those who had

radiographic evidence of AVN and collapse, but

maintained perfusion to the lateral corner of the

femoral head. Labs completed prior to initiating each

treatment cycle included: complete metabolic panel,

complete blood count, and ionized calcium. Dosing

and interval were age based (Table 1), and the first-

ever dose was half of each of the subsequent doses

and given in the pediatric intensive care unit. The

first-ever dose was given in the pediatric intensive

care unit due to concern for hypersensitivity reaction.

Besides this first dose, Pamidronate was given in our

outpatient infusion center on days 2 and 3, and

thereafter. During infusions, routine vitals were

measured. Infusions were given for three consecutive

days every 2-4 months, depending on age.

Following each cycle, ionized calcium and complete

blood count levels were analyzed. Calcium was

monitored closely due to the risk of hypocalcemia

with Pamidronate infusions. Physical and

occupational therapy needs were also evaluated at

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every treatment cycle. X-rays were completed every

3-6 months while on Pamidronate therapy to evaluate

for improvement.

Results: Four patients followed at our institution

developed AVN with perfusion preserved at the

lateral corner of the femoral head. These patients

received Pamidronate infusions and monitoring via

blood work and x-rays. Each of these patients had

labs (CMP, CBC, iCa) drawn prior to each cycle and

(iCa and CBC) after each cycle. Only one patient had a

drop in his calcium (iCa <1), which necessitated a

delay of the administration of Pamidronate by one

month, as well as adding calcium carbonate

supplements three times per day. Two patients also

developed hypovitaminosis D, one prior to starting

Pamidronate therapy and one patient 1.5 years after

completion, which was corrected.

The full course of Pamidronate therapy is two years,

however, it could be stopped earlier if there was

evidence of resolution of AVN on imaging (x-ray or

MRI). The femoral head shape was round and

spherical, and each patient had resolution of AVN

radiographically and symptomatically after treatment.

As shown in Table 2, there were varying lengths of

treatment. Most of the patients had clinical and

radiographic resolution of AVN prior to two years,

however one patient did require the full treatment

course of two years.

Conclusion: Avascular necrosis is an unfortunate

complication of SCD. Due to the pathophysiology of

the disease, red blood cells have a sickle shape and

can cause congestion within vasculature, causing pain

crises, stroke, and even necrosis. The femoral head is

a common place for avascular necrosis to occur, due

to decreased collateral circulation.3 This complication

can lead to long-term effects, such as hip destruction

and need for surgical intervention. Thus, detection

and treatment of AVN early in its course is important

to prevent invasive therapies such as core

decompression or hip replacement. Pamidronate is a

bisphosphonate that acts by preventing bone

reabsorption by blocking hydroxyapatite breakdown,

as well as causing osteoclast apoptosis.4 In other areas

of AVN in children such as Perthes disease, it has been

shown that if the lateral corner of the femoral head is

preserved, outcomes of AVN are much better.5 It is

due to this finding that pamidronate is used to

preserve the lateral corner of the femoral head in

AVN in SCD. Because there is a decrease in bone

breakdown, it is important for vitamin D and calcium

to be monitored so that they do not become

pathologically low. It is unclear how pamidronate

helps resolve AVN of the femoral head in SCD.

However, success could be through strengthening of

surrounding bone and decreasing further micro-

breaks, thereby preserving perfusion to healthy bone.

Limitations include: small sample size of our

comprehensive sickle cell population, and lack of

randomized clinical trials. Strengths include:

standardized protocol based on age.

Through our study, we show that Pamidronate is

effective in treating AVN of the femoral head, on the

condition that the lateral corner has preserved

perfusion. By using Pamidronate, one can delay the

need for more invasive modalities such as core

decompression or hip replacements. At this point,

four years is the longest a patient has been removed

from Pamidronate therapy and with no surgical

intervention. Our hope with this case series is to

share our success with using Pamidronate to treat

AVN in children with SCD, and for this therapy to be

further investigated.

Resources

1. Martí‐Carvajal AJ, Solà I, Agreda‐Pérez LH. Treatment for avascular necrosis of bone in people with sickle cell disease. Cochran Database of Systematic Reviews. 2016; 8(CD004344). Doi: 10.1002/14651858.CD004344.pub6

2. Plotkin H. Growth in osteogenesis imperfecta. Growth, Genetics & Hormones. 2007; 23 (2): 17-23. ISSN 1932-9032.

3. Adesina O, Brunson A, Keegan THM, Wun T. Osteonecrosis of the femoral head in sickle cell disease: prevalence, comorbidities, and surgical outcomes in California. Blood Adv. 2017;1(16):1287-1295. Published 2017 Jul 11. doi:10.1182/bloodadvances.2017005256.

4. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and

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role in clinical practice. Mayo Clin Proc. 2008;83(9):1032-45. doi: 10.4065/83.9.1032

5. Kollitz KM, Gee AO. Classifications in brief: the Herring lateral pillar classification for Legg-Calvé-Perthes disease. Clin Orthop Relat Res. 2013;471(7):2068-72 .

Age Dosage Interval

<2.0 years 0.37 mg/kg/day for 3 days 2 months

2.1-3.0 years 0.56 mg/kg/day for 3 days 3 months

>3.1 years 0.75 mg/kg/day for 3 days 4 months

Table 1: Dosing chart based on age2

Patient Age at Treatment Start Length Cycles

1 27 months 12 months 4

2 6 years 24 months 6

3 9 years 6 months 3

4 15 years 20 months 5

Table 2: Treatment length and number of cycles of each patient

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JSCDH-D-19-00002 ARGININE THERAPY IMPROVES MITOCHONDRIAL FUNCTION IN CHILDREN WITH SICKLE CELL

DISEASE AND VASO-OCCLUSIVE PAIN

Authors: *Morris CR1,2, Brown LA1, Wang Y3,

Dampier C1,2, Watt A2, Kumari P1,2, Figueroa J1,

Zmitrovich A2, and 3Shiva S1,

Affiliations: 1Emory University School of

Medicine, Atlanta, GA, 2Children’s Healthcare of

Atlanta, Atlanta, GA, 3University of Pittsburgh, Pittsburgh, PA,

Background: Vaso-occlusive pain episodes (VOE) are the leading cause of emergency department visits and hospitalization in patients with sickle cell disease (SCD). Our prior work has demonstrated that patients in VOE are arginine deficient and that arginine therapy significantly decreases total intravenous (IV) opioid use and improves pain scores in children with SCD during hospitalization. Mechanisms remain unclear, but may be due to stimulation of nitric oxide production. The Shiva lab has reported altered mitochondrial function in SCD patients vs healthy controls; decrease in mitochondrial electron transport Complex V activity leads to decreased respiration and increased detrimental oxidant production. We hypothesized that arginine therapy improves mitochondrial function during VOE.

Methods: Twelve subjects with HbSS or 0-thalassemia hospitalized for VOE (age male, 83% HbSS, 92% on Hydroxyurea) were randomized to treatment utilizing one of 3 dosing schemes of Arginine: 1) 100mg/kg IV three times/day (TID,n=3); 2) loading dose (200mg/kg) then 100mg/kg TID (n=5); or 3) loading dose (200mg/kg) followed by continuous infusion (300mg/kg/day) until discharge (n=4). Platelet rich plasma was isolated and stored at baseline presentation to the emergency department for VOE and hospital discharge for each subject and mitochondrial activity, protein expression, as well as protein carbonyls were measured. Results: Compared to a cohort of SCD patients in steady state, all subjects in VOE had a significantly decreased complex V activity (Fig1A). Notably, complex V activity was increased at discharge in subjects with VOE treated with arginine in all 3 dosing schemes, with greatest increase when utilizing a

loading dose. (Fig1B, p<0.001). While complex IV and citrate synthase activities were not changed in VOE platelets vs. steady state (data not shown), the activities of these enzymes were significantly increased in VOE subjects after arginine treatment when utilizing a loading dose( Fig1C-D, p<0.01). These changes are not due to increased mitochondrial number as quantification of mitochondrial DNA before and after arginine was not different (Fig1E). Complex V protein expression was also unchanged after arginine treatment (data not shown). However, arginine therapy did significantly decrease levels of protein carbonyls in platelet rich plasma across all treatment doses (Fig1F, p<0.01), suggesting a decrease in oxidative stress. Conclusion: These data demonstrate for the 1st time that arginine therapy increases mitochondrial activity and decreases oxidative stress in children with SCD/VOE. This novel mechanism may contribute to decreased pain and ultimately less opioid requirement after IV arginine treatment during VOE.

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Figure 1

A B

C D

E

p=0.002 P<0.001

F

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JSCDH-D-19-00007 BEYOND PAIN: THE SYMPTOMS AND IMPACTS OF SICKLE CELL DISEASE ON CHILDREN AND THEIR CAREGIVERS

Authors: Clark Brown, MD

1; Michael Callaghan, MD

2;

Sarah Clifford, PhD3; Farida Abudulai, BA

1; Ze Cong,

PhD4; Kellee Howard, MSc

3; Marzena Jurek, MS

4; Kelly

Lipman, MPH3; Ramya Pratiwadi, MS

3

Affiliations: 1Children's Healthcare of Atlanta,

Atlanta, GA, UNITED STATES, 2Wayne State

University School of Medicine, Detroit, MI, UNITED

STATES, 3ICON plc, San Francisco, CA, UNITED

STATES, 4Global Blood Therapeutics Inc, South San

Francisco, CA, UNITED STATES

Background: Sickle cell disease (SCD) affects

approximately 1 in every 400 African American

children born in the US and causes chronic

anemia, hemolysis, and vaso-occlusive crises

(VOCs), resulting in significant morbidity and

associated mortality. VOCs have traditionally been

the clinical endpoint used in SCD; however, they

do not capture the full spectrum of SCD symptoms

and the impacts experienced by children and their

caregivers, which tend to be underreported in the

literature. This study sought to comprehensively

summarize the most important symptoms

experienced by children with SCD and the impacts

on the daily lives of children and their caregivers.

Methods: Qualitative in-person interviews were

conducted in children with SCD and their

caregivers, recruited from two clinical sites in the

US. Children aged 2–11 years diagnosed with SCD

with ≥1 VOC in the past year requiring a

hospitalization/medical encounter were eligible.

Institutional Review Board approval was obtained

at each site. Semi-structured interview guides

(one for children, one for caregivers) consisting of

exploratory open-ended questions were

developed using results from a literature review.

De-identified interview transcripts were analyzed

using a qualitative analysis software. Saturation of

concepts was assessed.

Results: Children (N=7, aged 8–11 years, 86% female)

were diagnosed with SCD as newborns, with

homozygous sickle hemoglobin (HbSS, n=6) or sickle

beta 0-thalassemia (HbSβ0, n=1). Caregivers (N=16)

responsible for children (aged 2–11 years) with SCD

primarily were mothers (81%) and were employed full

time (69%). Concept saturation was reached for both

symptoms and impacts among both children and

caregivers. Children reported eight symptoms, most

commonly bodily pain (7/7), fatigue (6/7), pain crisis

(5/7), and difficulty breathing (5/7). Caregivers

reported 15 symptoms, most commonly bodily pain

(15/16), pain crisis (15/16), fatigue (13/16), fever

(13/16), headaches (9/16), acute chest syndrome

(8/16), and yellow eyes (7/16). Children reported 23

impacts, including general life with SCD, family, sleep,

emotional and physical functioning, school, and

recreational activities. The most common impacts

reported by children were sadness (6/7), decreased

school attendance and performance (5/7), and

inability to participate in activities that friends do

(5/7). Caregivers reported 29 impacts, with school

absences (15/16), caregiver burden (14/16), sadness

(11/16), and change in energy level (10/16) the most

frequently reported.

Conclusions: This study identified a range of salient

SCD symptoms beyond pain (e.g. fatigue) and their

substantial impact on children with SCD and their

caregivers. Additional treatment and care strategies

to address the full symptomatology of SCD are

needed.

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JSCDH-D-19-00008

STREAMLINING CARE FOR REFUGEE AND IMMIGRANT CHILDREN WITH SICKLE CELL DISEASE AND THALASSEMIA

Authors: Nazia Tabassum Iqbal, MD; Areli Ramphal, LMSW; Emily Cowden APRN; Larri Harris Rn, APRN; Lindsey MacDonald LMSW; Ibrahim Ahmed, MD; Gerald Woods MD

Affiliations: Children’s Mercy Hospital and Clinics

Background: Sickle cell disease (SCD) and thalassemia are the most common form of monogenic inherited hemoglobinopathies. Their prevalence is higher in the old world and malaria-endemic areas. Due to immigration, the distribution of SCD and thalassemia has been changing worldwide. For many immigrants and refugees, the following factors can be barriers to health care access:

Poor economic background

Prior adverse living conditions

Lack of education

Non-English speaking

Availability of prior health records

We seek to bring attention to the challenges encountered in caring for immigrant children with SCD in Kansas City.

Method: Twenty immigrant/refugee with SCD and thalassemia were followed at Children’s Mercy Kansas City.

Results:

Identified/used consistently a primary/proficient interpreter. Telephone/video services are also used.

Handouts/instructions in native language

Encourage participation in research studies

IRB consent translated to native language

Utilized local government and community resources

Donation drives

Identification of primary care providers, preferably culture competent and qualified bilingual staff (QBS)

Facilitating medication pick-up or mailing services

Financial assistance and counseling

Culturagram psychosocial assessment

Neurocognitive testing

Coordination of care with multi-disciplinary teams

Social-work case management

Conclusions: Health burden of hemoglobinopathies is expected to increase with immigration in the USA. Unfamiliarity with the health care system, underutilization of available services, and lack of understanding of immigrants/refugee health care requirements and clinical complications are major factors to be addressed.

We recommend screening all immigrant children from countries with a high prevalence of hemoglobinopathies using hemoglobin electrophoresis at initial visit. Patients that require continuous health care as transfusions or clinical follow up to be followed by hematologist until a confirmatory electrophoresis is performed.

Immigration from countries with a high hemoglobinopathies prevalence contributes to the addition of S gene and thalassemia genes into the general population. Awareness of the disease prevalence within the patient’s country of origin and efficient prevention programs could reduce long-term severe complications in immigrant population

Strategies to better acquaint the immigrant patients with the health care system are required. Effective communication with immigrant patients in their native language using interpreters is essential. Maximizing use of available resources using targeted outreach, combined with financial assistance and counseling, can help improve outcomes among the immigrant population.

Overcoming the linguistic, financial and cultural barriers, will significantly sustain effective communication in the holistic treatment strategy for

immigrant population.

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JSCDH-D-19-00010 ESTABLISHMENT OF NEUROCOGNITIVE TESTING PROTOCOL IN CHILDREN WITH SICKLE CELL DISEASE

Authors: Lea Ventura PhD 1,2

, Sharice

Bradford,M.Div,EdD1, Alison Oh, MA

2, Jocelyn Mallard,

APN1, Ronisha Edwards-Elliott, MSW

1, Lewis L. Hsu,

MD1, and Angela Rivers MD, PhD

1

Affiliations: 1Department of Pediatrics and

2Department of Psychiatry, University of Chicago, Il

Background: The neurocognitive sequelae of stroke in

children with SCD are characterized by pervasive

impairments, including decrements in general

intellectual functioning, language and verbal abilities,

visual-motor and visual-spatial processing, memory,

attention and executive functions, and academic

achievement. Impairments in sustained attention and

concentration, executive functions, and processing

speed are also common in youth who experience silent

infarcts. SCD patients are also at increased risk for

learning difficulties, particularly in reading and

mathematics. Although there is some awareness of

these deficits, the most effective and efficient method

of referring and evaluating SCD patients for

neurocognitive problems has not been well

established. The current program aimed to examine

patient utilization of testing services and outcomes.

Methods: To accomplish this, the team at University of

Illinois Hospital and Health Sciences System distributed

flyers about neurocognitive testing in a mass mailing.

In addition, 69 families had a practitioner who spoke

with patients and families during their regular

hematology appointment to explain the goals of

neuropsychological testing. The flyers were given

again at this time.

Results: Of those 69 patients, 24 patients age 10-24

have received clinical evaluation. Gender was equally

distributed. Of the patients tested, 25% had a history

of stroke, 41% were physician referred for the

suspicion of neuropsychological problems, and the

remaining 33% were referred for asymptomatic

screening. Across the domains of intellectual

functioning, executive functions, and academic skills,

patients with a documented history of stroke exhibited

the most severe deficits, with an IQ in the impaired

range (FSIQ=63, SD=3.3), significant executive deficits,

and impairments in reading (SS=59) and math (SS=69).

Physician referred patients fared slightly better, with

borderline to low average intellectual abilities

(FSIQ=79, SD=13.1), fewer executive deficits, and low

average reading (SS=89) and math (SS=82). Patients

referred for a routine screen fared best, with average

intellectual functioning (FSIQ=92, SD=3.4), executive

functions, and reading (SS=92) and math skills (SS=97).

Of the 45 patients that received flyers but did not go

for testing: 8% of patients have a history of stroke,

42% were physician identified and the remaining 46%

were referred for asymptomatic screening.

Conclusions: Patients referred for routine screening

fared the best on measures of intellectual abilities,

executive functions, and academic skills, followed by

physician referred patients, and then patients with

documented stroke. Children who were asymptomatic

were less likely to schedule appointments for testing.

Thus it appears that it is more difficult to implement

testing for children whose families are asymptomatic.

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JSCDH-D-19-00011 TREATMENT OF MODERATE TO SEVERE ANEMIA IN SICKLE CELL DISEASE:

RESULTS FROM A 2018 US PATIENT CHART ANALYSIS

Authors: Robin Howard, MBA

1; Suzanne Litke, MSS

2;

Deepa George, PhD2; Kenneth R. Bridges, MD

1

Affiliations:1Global Blood Therapeutics Inc, South San

Francisco, CA, UNITED STATES, 2NAXION,

Philadelphia, PA, UNITED STATES

Background: Sickle cell disease (SCD) is a lifelong,

debilitating disorder that affects approximately

100,000 patients in the US. SCD is challenging to

manage, and there remains a lack of evidence to

guide the management of SCD at the community

level, where physicians may have limited treatment

experience and support. Although there are

recommendations for managing patients with SCD

with vaso-occlusive crises, there is an unmet need

in treating patients with SCD with moderate to

severe anemia. This analysis reviewed national

treatment patterns of SCD in moderately

(hemoglobin [Hb]=7–10.5 g/dL) and severely (Hb <7

g/dL) anemic versus non-anemic (Hb >10.5 g/dL)

patients in the academic and community settings.

Methods: Patient charts were obtained from 300

US physicians—primary care practitioners,

pediatricians, and adult and pediatric

hematologists—64% of whom practiced in the

community setting. The 870 charts submitted by

physicians responsible for these patients’ SCD-

related treatment decisions met the following

predefined criteria: patients were >2 years of age,

followed for ≥1 year, seen in the clinic within the

previous year for a routine outpatient visit, and

had not received a bone marrow transplant.

Results: Of the 870 patients assessed (74% adult), 52%

had the homozygous Hb SCD genotype HbSS, and 28%

had the heterozygous Hb genotype HbSC. Most

patients had moderate or severe anemia (48% and

12%, respectively), determined by their most recent

lab results. Although patients with SCD tend to be

anemic, the Hb levels in 12% of patients were not

assessed during the previous 2 years. At the time of

analysis, more anemic patients (61%, Hb ≤10.5 g/dL)

than non-anemic patients (37%) were prescribed

hydroxyurea for symptomatic treatment. Similarly,

more anemic patients (24%) received chronic

transfusions than non-anemic patients (16%). Among

both anemic and non-anemic patients, 16% received

chronic transfusions for anemia. The most common

reasons for chronic transfusions were anemia (79%),

prior stroke (9%), and elevated transcranial Doppler

scores (11%), a risk factor for stroke in patients with

SCD. Finally, 19% of all patients received

erythropoietin therapy, of whom 36% received

erythropoietin for ≥1 year.

Conclusions: Most patients with SCD in this analysis

had moderate to severe anemia, and the observed use

of erythropoietin therapy, among other non-disease-

modifying treatments, is strong evidence of a clear

unmet need to improve anemia in these patients. Even

non-anemic SCD patients may benefit from an agent

that targets hemolysis and anemia.

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JSCDH-D-19-00013 TOBACCO SMOKING AS PROGNOSTIC INDICATOR IN SICKLE CELL DISEASE:

A RETROSPECTIVE ANALYSIS OF PROSPECTIVELY COLLECTED DATA

Authors: Nityam Rathi, Seyed M. Nouraie, Ph.D., and

Gregory J. Kato, MD.

Affiliation: Department of Medicine and the Heart,

Lung and Blood Vascular Medicine Institute, University

of Pittsburgh School of Medicine

Background: Sickle cell disease (SCD) is an inherited

blood disorder characterized by abnormal sickle-

shaped red blood cells. Sickling creates a higher

tendency in red blood cells to aggregate and stick to

vascular beds, making vascular beds a target organ in

SCD. In preliminary screening for a current drug study

of high vascular risk SCD patients (characterized by

high blood pressure, high estimated pulmonary blood

pressure, proteinuria, and early mortality) at UPMC,

smokers anecdotally seemed overrepresented. To

date, there has not been a broad-based SCD study of

smoking and vascular disease outcomes. We

hypothesized that smoking could be linked to four

important health outcomes that characterize high

vascular risk.

Methods: Relevant prospectively-collected data from

the walk-PHASST multi-center clinical trial

(ClinicalTrials.gov Identifier NCT00492531) were used

for this analysis. 672 adult SCD patients (53% female,

47% male; all of age 18-70 years) were separated into

three groups: current smokers, former smokers, and

non-smokers. In each group, normal distribution for

continuous variables were inspected using histograms

with addition of a normalized smoothed curve and

Shapiro-Wilks test. Parametric or nonparametric

analyses were then used for data analysis. P-values

were calculated using either ANOVA, or Chi-Squared

tests. Additionally, a survival analysis for time to death

by smoking status was performed using the Kaplan-

Meier and log rank test. Analyses were performed in R

and Stata.

Results: About 15% of adults with SCD were active

smokers, and 67% had never smoked. In univariate

analyses, age, gender, systolic blood pressure,

tricuspid regurgitation velocity (TRV, as a noninvasive

marker of pulmonary hypertension), and estimated

Glomerular Filtration Rate (EGFR), and pack-years

show significance or relevant trends. Patients who

never smoked are significantly younger, more likely to

be female, have a lower systolic blood pressure, and

have greater estimated glomerular filtration rate.

Upon adjustment for age and gender, current and

former smokers had a slightly higher TRV. Despite a

very limited duration of follow up, over 20 months the

survival analysis shows a trend toward lower mortality

in patients who have never smoked, although it is not

statistically significant (P=0.37).

Conclusions: SCD smoking status demonstrates

statistically significant associations with indicators of

hypertension, pulmonary hypertension and renal

function; and a non-significant relationship to

mortality during follow-up. However, neither causation

nor detailed associations can be determined from this

limited dataset. The results of this exploratory

retrospective analysis are hypothesis-generating, and

support a need for further investigation of the

consequences of smoking upon SCD outcome.

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JSCDH-D-19-00016 PRESENTING ARISE (THE AFRICAN RESEARCH AND INNOVATIVE INITIATIVE FOR SICKLE CELL EDUCATION PROJECT)-

“IMPROVING RESEARCH CAPACITY FOR SCD HEATH CARE SERVICE IMPROVEMENT”

Authors: Lewis L. Hsu, Bola Ojo, Baba Inusa, Stephanie Lauren Quirk, Fedele Bonifazi Affiliations: University of Illinois, SCORE Foundation, Guys and St. Thomas Hospital, Fondazione Gianni Benzi Onlus Background: Sickle cell disease (SCD) is among the world’s most common serious inherited diseases with more than 300,000 annual births

1, 85% are born

in sub-Saharan Africa. SCD accounts for 8-16% of all-cause mortality in childhood in Sub-Saharan Africa even though it represents 2% or less of all births in the region. Increasing migration from high prevalence areas of Africa to European countries like UK, Italy, Greece and Republic of Ireland has grown their SCD population. The outcome of SCD in high-income countries differs markedly with low-middle income countries where less than 50% of affected births will not survive beyond the 10

th birthday.

Multiple factors account for these disparities including early diagnosis by newborn screening (NBS), prophylactic penicillin and comprehensive follow up. The optimal care for patients with SCD in Africa should incorporate this approach plus laboratory capacity and blood banking services. The objective of ARISE is to establish a

multidisciplinary staff exchange program to foster

the sharing of best practice in NBS, diagnosis and

treatment leading to improvement in overall disease

outcome. The purpose is for a sustainable,

appropriate health service for those living with SCD.

Methods: This involves research staff exchange between 9 European Union (EU) institutions interacting with non-EU countries including Africa and US. Through work package tasks, staff on exchange visits (secondments) will evaluate the prevalence of SCD among populations; identify SCD specific genotypes and phenotypes; study existing NBS and early infant screening; study engagement with patients, communities especially mothers and policy makers to determine barriers to NBS; establish laboratory diagnosis, quality assurance systems for population screening. Results: The 4-year project launched in January 2019.

Visiting exchanges at University of Illinois at Chicago

which focus on NBS and clinical care began in March

with the study of Implementation science strategies,

community health worker programs and stakeholder

engagement observations. A comparison study of

USA/UK Community Health Worker (CHW) role will

facilitate adaptation and training for settings in Africa

to include developing a CHW curriculum.

Conclusions: The multi-directional exchanges will foster new collaborative, institutional partnerships, promote scientific and technological SCD research cooperation between Africa, Europe and USA and build capacity towards sustainable improvement in health-related outcomes. Through ARISE interagency exchange program, interdisciplinary gender balanced teams will work with policy-makers in Africa to examine the effectiveness of a community-based approach to SCD using the tools of implementation science to understand the local context and health systems.

Acknowledgement – This project has received

funding from the European Union’s Horizon 2020

research and innovation programme under the Marie

Skłodowska-Curie grant agreement No 824021.

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JSCDH-D-19-00017 TRACKING EDUCATIONAL PROGRESS IN OUR SICKLE CELL POPULATION

Authors: Jun Zhao DO1,2

, Spencer Moorman MSW1,2

,

Esther Knapp MD1,2

,Kerry McGowan MD1,2

, Laura

Massie APRN1, Ashok Raj MD

1,2

Affiliations: 1

University of Louisville School of

Medicine, Louisville, KY, 2

Norton Children’s Hospital,

Louisville, KY

Background: An important aspect of improving care in

sickle cell disease (SCD) patients is comprehensive

patient education regarding disease pathophysiology,

symptom management, and resources for treatment.

The emergency department (ED) is often the first line

resource for management of symptoms such as acute

pain crisis, and some patients can develop the

perception that they are able to receive all of their

necessary sickle cell medical care in the ED setting. As

pediatric patients with sickle cell disease grow older,

coordinated transition of care and appropriate

utilization of care resources are crucial to their long-

term success.

Methods: A transition of care program was

implemented in our pediatric sickle cell clinic to help

assess each patient’s readiness to transition to an

adult hematology provider. As a part of their

readiness for transition of care assessment, a 10-item

sickle cell general knowledge quiz is given. The quiz

includes questions regarding the genetics of sickle

disease, potential triggers for crisis, manifestation of

disease in different organ systems, and resources for

receiving care. In addition, a retrospective chart

review was performed to collect patient disease

genotype, number of emergency department visits,

and reasons for each visit between 2016-2018.

Results: There were 202 total ED visits with 97

individual patients in 2016 with the following genotype

breakdown: hemoglobin SS 64%; hemoglobin SC 24%;

hemoglobin SB0 5%; hemoglobin SB

+ 7%. The numbers

for 2017 and 2018 showed a minor decline in yearly

visits across all genotypes. The knowledge quiz

administered in 2017-2018 to 30 patients aged 13-18

years was revealing in two areas: 1) 50% (15/30) of

patients believed that they can receive all of their

medical care from the ED and 2) 27% (8/30) patients

misidentified complications from their disease.

Conclusions: Although improvements have been

made in educating and preparing sickle cell patients

for transitioning to adult care, areas in need of

improvement remain for example, increasing their

baseline knowledge of SCD and management. This

study has identified educational gaps that exist as part

of the transition process. With this knowledge, we

hope to improve current education efforts of sickle cell

patients, particularly as they transition from pediatric

to adult hematology care.

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JSCDH-D-19-00018 IMPACT OF VASO-OCCLUSIVE CRISES ON QUALITY OF LIFE, HEALTHCARE RESOURCE

UTILIZATION AND WORK PRODUCTIVITY IN SICKLE CELL DISEASE PATIENTS

Authors: Rizio A

1, Bhor M

2, Lin X

1, White M

1,

McCausland KL1 Paulose J

2, Nandal S

2, Halloway R

3,

Bronté-Hall L4

Affiliations: 1Optum, Johnston, RI, USA,

2Novartis

Pharmaceuticals Corporation, East Hanover, NJ, USA,3

Formerly Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA,

4Foundation for Sickle Cell Disease

Research, Hollywood, FL, USA

BACKGROUND: Sickle cell vaso-occlusive crises (VOCs) are painful episodes experienced by patients with sickle cell disease (SCD) and triggered by multicellular adhesion that block or reduce blood flow. This study aimed to explore the relationship between VOCs and patients’ quality of life (QoL), healthcare resource utilization (HCRU), and work productivity.

METHODS: The analytic sample included adult patients

with SCD (N=252) who completed a cross-sectional

online survey. QoL and VOC frequency and severity

were assessed with the Adult Sickle Cell Quality of Life

Measurement Information System (ASCQ-Me).

Patients answered questions regarding employment

impacts and completed the Workplace Productivity

and Activity Impairment: Specific Health Problem

(WPAI-SHP), which assesses productivity over the past

7 days. Patients also reported the number of times

within the past 12 months they used different

healthcare services to treat VOCs. Patients were

stratified according to the number of VOCs they

experienced within the past 12 months and the

severity of their VOCs measured by ASCQ-Me pain

severity score. Kruskal-Wallis tests were used to

evaluate differences in ASCQ-Me and WPAI domains

and measures of HCRU according to VOC frequency

and severity.

RESULTS: Patients with more frequent VOCs reported

greater impacts on all ASCQ-Me domains than patients

with less frequent VOCs (p<.05 for all). No differences

were observed in the number of times patients visited

a healthcare provider for VOCs (p=.087). Patients with

more frequent VOCs reported more ER visits and

overnight hospital stays than patients with less

frequent VOCs (p<.05 for both). Fifty-eight percent of

patients reported that SCD negatively impacted their

employment status; 73% of patients with ≥4 VOCs in

the past year reported negative impacts compared to

45% of patients with 0-3 VOCs. Patients with more

frequent VOCs reported greater absenteeism and

overall productivity loss than patients with less

frequent VOCs (p<.05 for both). Presenteeism did not

differ according to VOC frequency (p=.132). Significant

impacts on QoL, HCRU, and work productivity were

observed when stratifying by VOC severity; the pattern

of results was similar to those found when stratifying

by VOC frequency.

CONCLUSION: Patients with more frequent or severe

VOCs experience deficits in QoL and utilize costlier

healthcare services to treat VOCs. Patients with more

frequent or severe VOCs also missed more work in the

week preceding survey administration than patients

with less frequent or severe VOCs. Future research

should examine the impact of SCD-related

complications on the relationship between VOCs and

QoL, HCRU, and work impairment.

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JSCDH-D-19-00022 TIERED ORAL THERAPY APPROACH FOR SICKLE CELL DISEASE VASO-OCCLUSIVE CRISIS MANAGEMENT

Authors: Margaret Guy, MD1; Lauren Cherry Magee,

PharmD, BCPS2; Sarah Hartigan, MD

1; Mica Ferlis,

MS,RN1; Wally Smith, MD

1; Daniel Sop, MS

3

Affiliations: 1 Division of General Internal Medicine,

Virginia Commonwealth University Health System,

Richmond, Virginia , 2 Department of Pharmacy,

Virginia Commonwealth University Health System,

Richmond, Virginia, 3Department of Biomedical

Engineering, Virginia Commonwealth University,

Richmond, Virginia

Introduction: Sickle cell disease is responsible for

>200,000 ER visits a year most of which are due to

pain. Although opioids remain the standard therapy

for the treatment of pain, there is little in the literature

that has studied opioid therapy in Sickle Cell Patients

as a predictor of outcomes; mainly healthcare

utilization. To this end, the hospital medicine team of

the Virginia Commonwealth University Health System

piloted a standardized approach to pain management

on one inpatient unit using a Tiered Oral Therapy

(TOTP) approach with goals to impact utilization

metrics such as the length of stay, 30 day readmission

rate while improving quality of care for patients

admitted with SCD pain crisis.

Methods: The treatment plan included long-acting oral

opioids for basal coverage, patient-controlled

analgesia (PCA), and immediate-release oral opioids

for breakthrough pain. In phase 1, we rapidly achieved

adequate analgesia by up-titrating the PCA every 2 to 4

hours. Patients may receive one to two times their

home oral immediate release opioids to aid with

breakthrough pain. After adequate analgesia is

achieved, we progressed to phase 2 where we held

the course to allow patients 24 hours of rest and

recovery. During phase 3, we decreased the PCA by

25% every 12 hours by initiating the patient’s home

oral immediate release opioids scheduled around-

the-clock with additional immediate release dosing

for breakthrough pain at a dose reduced from the day

of admission. The PCA continued to be tapered by 25%

of the maximum dose every 12 hours during phase 4

until the day of discharge which was phase 5. During

all phases, patients were continued on their home oral

long-acting opioid for basal coverage.

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Results: As a result of this implementation, we noted a

3.11 days reduction in LOS from implementation to

conclusion on the pilot unit with a mean LOS of 5.589

(SD=0.94, CI=4.909, 6.268). While patient satisfaction

was not directly measured as related to the algorithm,

when asked whether they noticed changes to their

care during their hospital stay patient answered: Yes

72.2%, No 27.8%. When asked if they felt that the

team was working together to address their vaso-

occlusive crisis pain, patients answered: Yes 94.1%, No

5.9%. 30 day readmission rate was reduced by 6.36%

amongst the patients who participated on the TOTP.

Conclusion: The use of TOTP was associated with

reduced length of stay and 30 day readmission rate for

patients that participated in the tiered oral therapy.

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JSCDH-D-19-00024

TRANSITION FROM PEDIATRIC TO ADULT SICKLE CELL DISEASE CARE: A SINGLE-CENTER

MODEL FOR TRANSITION IN RURAL POPULATIONS

Authors:

1Nnenna Badamosi, MD, MPH;

1Dominik

Barnes, BA; 1Betty Pace, MD

Affiliations: Department of Pediatrics, Augusta University, Augusta, GA

Background: Transition to adult care for young adults

with sickle cell disease (SCD) in rural populations

presents unique challenges. Lack of skilled providers

and limited access to subspecialty care hinder

successful transition and place these patients at higher

risk of morbidity than their peers. The Augusta

University (AU) transition program consists of pediatric

hematologist, transition coordinator, SCD nurse and

social worker, who provide care through the Pediatric

Comprehensive Sickle Cell Program. We piloted an off-

campus program through bimonthly outreach clinics in

rural South Georgia to facilitate successful transition to

adult care. Our objective was to evaluate the feasibility

and effectiveness of annual in-person transition

coordination in this underserved population with

limited access to care.

Method: We identified eligible teenage patients

scheduled for standard of care at four SCD outreach

clinic sites held in Waycross, Dublin, Albany and

Valdosta, GA in September 2018. Transition

coordinator engaged with patients during wait times

and enrolled them in program. She conducted

transition readiness assessments, provided

educational materials on SCD and transition to adult

care, available health insurance plans and information

on adult SCD providers. Patients were then

transitioned to adult care based on age, high school

graduation status and readiness assessment. Patients

provided feedback through satisfaction surveys

following the visit. Subsequently, the transition

coordinator performed telephone follow up 30 and 90

days after the outreach clinic and/or transition to adult

care.

Results: Thirty-five teenagers/young adults were

scheduled for care, of whom 21 (60%) kept their

appointments. All patients were African American with

a median age of 15 years (13 – 21 years) and 12 males

(57%); the transition coordinator enrolled all patients

in the program. Four (4/21) patients aged 18 – 21

years were transitioned to adult sickle cell providers.

On satisfaction surveys, all 21 respondents agreed or

strongly agreed when asked about ease of

understanding of educational materials provided,

specificity of information for SCD and whether their

questions were addressed appropriately. They

reported overall satisfaction with the transition

program with no significant changes in wait times or

duration of clinic appointments. Three out of four

(75%) of transitioned patients had seen or scheduled

appointments with adult providers by 90-day follow-

up.

Conclusion: For urban pediatric sickle cell programs

with rural outreach clinics, focused care on adolescent

patients can facilitate successful transition to adult

care. In-person transition coordination during

outreach clinics represents a cost-effective model for

providing transition care when a dedicated transition

clinic is unavailable, or limited by existing resources.

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JSCDH-D-19-00025 A SMART PHONE BASED INTERVENTION TO IMPROVE OUTCOMES IN SICKLE CELL PATIENTS WITH FREQUENT HEALTH CARE UTILIZATION

Authors: Maya Crawford, Kyle Kidwell, Michael Pope, Camila Albo, Latanya Bowman, Leigh Wells, Nadine Barrett, Pritam Bora, Hongyan Xu and Abdullah Kutlar, Affiliation: Augusta University Background: A small group of patients with sickle cell disease (SCD) have frequent ED visits and hospitalizations, mostly with pain episodes, and are responsible for a significant health care costs. These patients comprise 5-10% of the total patient population in many centers, have significant morbidity, poor quality of life, and higher rates of mortality. We recently studied the characteristics of 28 patients with

visits/hospitalizations per year) and found that both biologic and behavioral/psycho-social factors contributed to high utilization phenotype (Higher WBC and ANC, higher bilirubin, lower MCV and Hb F, poor adherence to HU, lower educational level, higher anxiety and depression scores, and poorer coping skills compared to patients with low utilization). We studied the efficacy of a smart phone based app, Medisafe, in improving the outcomes in a group of patients with high health care utilization. Methods: 28 patients (14 males, 14 females, ages 19-60, median 30.5) were enrolled in the study, conducted at the Adult Sickle Cell Clinic, Center for Blood Disorders, Augusta University. Subjects were consented during clinic visits, and downloaded the

Medisafe app to their smart phones. This app was used to set medication reminders (primarily HU), but could also be utilized to record and communicate pain scores to the provider’s i-pad. The subjects were followed for a minimum of two months, and the preliminary results are reported here. Results: Compliance with the use of Medisafe was recorded and evaluated in a two month period. Overall, 20/28 patients (71.4%) were compliant to varying degrees and sent status reports, including daily pain scores, via Medisafe weekly. The number of ED visits and hospitalizations and laboratory values at baseline and at the end of intervention were compared. Although positive trends were observed in some parameters (Hb F, hemoglobin, MCV), none reached statistical significance. Conclusions: Frequent health care utilization in SCD is a significant problem, both from the standpoint of patients (poor outcomes, poor quality of life) and from a medical-economic (increased health care costs) point of view. We previously (Kidwell et al., Blood,…) showed that this is a multifactorial problem, and therefore will likely require a multi-disciplinary approach. The current study shows that a smart phone based approach to improve medication adherence, and to improve patient-provider communications is feasible with 71.4% compliance rate. Its efficacy in improving the outcomes in this patient group should be studied in a longer period of time.

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JSCDH-D-19-00027 PATIENT AND PARENT PERCEPTION ON SICKLE CELL TRANSITION OF CARE

Authors: Diana Rash-Ellis LSW, Opeyemi Kemiki Dada,

RN, APN, Steve Reader PhD, Sidnie Jacobs-Allen MSA,

Robin Miller MD, Colleen N. Keeler, BS,

Affiliations: Nemours Center for Cancer and Blood

Disorders, The National Institute of General Medical

Sciences of the National Institutes of Health under

Award Number P20GM109021

Purpose: To identify the key areas of need during

transition and to increase the knowledge base of our

Sickle Cell patients and their families in order to

improve our transitional program. The goal of this

assessment would be to enhance our current

transition clinic and increase the educational literacy

of our sickle cell population in preparation for

transition to adult care.

Background: Transition of care among chronically ill

patients is a complex process due to several issues:

dependency of the patient on their parents/guardians,

cognitive as well as psychosocial difficulties, and the

lack of continuity of care. The goal of medical

transition is to provide health care that is:

uninterrupted, coordinated, developmentally

appropriate, and comprehensive.

In response to issues with lack of engagement in

transition, we have attempted to understand patients

and parents perception on transition by conducting a

transitional workshop and support group. Based upon

the sickle cell workshop questionnaires during our

second transition workshop, it was noted by the teens

that attended the workshop that their primary

concerns were that they would be lost to care and that

the adult providers would not know them once

transitioned to adult care facilities. Parents identified

on their version of the questionnaire that they felt

their children would be successful in transition to adult

care from pediatric due to their continued

involvement with their child’s medical care. Some

parents did identify their concern with leaving the

pediatric facility due to having spent the majority of

their child’s medical care with the same providers in

the same pediatric system.

The data collected is based upon 20 questionnaires

completed by both parents and patients during

transitional workshop and support group. The parent

and patient were given questionnaires that consisted

of open ended and Likert scale questions that were

based upon their perception of how prepared they are

educationally for adult care.

Conclusion: Based on the data collected from the

questionnaires, we discovered that patient and parent

have limited understanding of transition of care and

the necessary skills needed to transition to adult care.

Both patient and parents expressed their concern

regarding transition from pediatric to adult care and

receiving care from unknown adult providers in an

adult facility. The information gathered from the

questionnaires will be used in the expansion of our

current sickle cell clinic and modification of the

structure and curriculum currently being used.

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JSCDH-D-19-00028 NEWBORN SCREENING DATA FOR SICKLE CELL DISEASE IN CALIFORNIA AND GEORGIA, 2004-2016:

IMPLICATIONS FOR HEALTH INTERVENTIONS

Authors: Aika Aluc, Mei Zhou, Angie Snyder, Susan

Paulukonis, David Wong, Mary Hulihan

Affiliation: Centers for Disease Control and Prevention

Background: Most incident sickle cell disease (SCD)

cases in the United States are identified through

newborn screening (NBS). The Sickle Cell Data

Collection (SCDC) program is a population-based,

longitudinal surveillance system for SCD that was

implemented in California and Georgia to collect

information from multiple data sources, including NBS

records. SCDC data can be used to identify changes in

sickle cell epidemiology and help target public health

resources and interventions.

Methods: We analyzed demographic and genotype

data for all individuals with SCD who were identified

by NBS in California or Georgia with a date of birth

during 2004 – 2016. A geographic trends analysis

(based on birth county) was conducted to compare the

number of SCD births occurring in high-population

Metropolitan Statistical Areas (MSAs) (defined for this

study as ≥2 million population) to SCD births occurring

in other MSAs. Based on 2017 U.S. Census population

estimates, there were five high-population MSAs in

California and one high-population MSA in Georgia.

Results: An average of 90 (range 68-117) SCD births

were identified per year in California and 156 (range

134-223) in Georgia. Forty-seven percent of the

newborns with SCD in California and 49% in Georgia

were female. The proportion of births by genotype did 0

+

thalassemia; the remaining 7% were other SCD

genotypes or the genotype was unknown. Overall, 83%

and 58% of SCD births occurred in high-population

MSAs in California and Georgia, respectively; these

percentages were consistent over time. For specific

high-population MSAs, decreases in SCD births were

observed from 2005-2009 to 2010-2014 in Los Angeles

(213 to 169 births) and San Francisco (67 to 45) and an

increase was observed in Riverside-San Bernardino (59

to 84). No significant changes were identified in the

other two MSAs in California or the one in Georgia.

Conclusions: There are sizeable numbers of newborns

diagnosed with SCD in both California and Georgia.

Most SCD births continue to be identified in high-

population MSAs; however, decreases in SCD births

were observed in select areas, notably Los Angeles and

San Francisco, and an increase was noted in Riverside-

San Bernardino. Data from SCDC are critical for

understanding changes in epidemiology that can

identify opportunities for targeted SCD interventions,

including workforce development, patient education,

and care across the lifespan.

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JSCDH-D-19-00030 ESTABLISHING A SICKLE CELL CENTER IN THE NEW YORK CITY (NYC) PUBLIC HOSPITAL SETTING

Author: Linda Bulone Affiliation: Queens Hospital Center Background: Sickle cell patients at Queens Hospital, a public hospital in NYC, historically had a very high readmission rate (defined as occurring less than 30 days from the prior admission). In this hospital the readmission rate for Sickle Cell patients was 63.9% - the highest readmission rate of ANY illness. A Sickle Cell Center was developed with the aim to lower readmission rates. Methods: The Sickle Cell Center was created to provide comprehensive, individualized, medical and psychosocial services for patients within a public hospital. A designated Hematologist Oncologist was assigned to oversee the program and a Nurse Practitioner (NP) was hired to care for all Sickle Cell patients referred to the Center and seen in the Emergency Room (ER). The NP was also tasked to educate staff in the ER and Inpatient Units on care of the Sickle Cell patient with the latest evidence-based practices on managing pain crisis in a timely manner. A Sickle Cell Support group was formed. Sickle Cell Program leaders also networked with Advocacy programs to provide patients with additional support and education as an outpatient. This Program is designed to promote managing the condition at home

to prevent severe crisis. Longitudinal data was collected over a 3 year period and was used to describe patient demographics, needs and services. Results were measured by the percentage of patients readmitted to the inpatient unit at year three. Results: By year three, 100% of the Sickle Cell patients were seen by Sickle Cell Program leaders directly from the ER or as outpatient referrals. Since its inception, 235 new Sickle Cell patients were served (128 female and 107 male adults). An average of twenty patients attend the support group. Percentage of patients that required readmission to hospital was 63.9% at baseline. By year three, readmission rates decreased to 33.3% - a 48% decrease. This translated to a $1.7 million dollar hospital cost savings. Conclusions: The Sickle Cell Center has been well integrated and accepted into the public hospital system and can be used as a model for health care delivery for this socio-economically challenged population. The results show that patients are able to live in the community, manage their condition and decrease the need to be readmitted by utilizing the education and support received as an outpatient. The results also show that this translates into significant savings for the hospital which justifies implementation of the program in other facilities.

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JSCDH-D-19-00032 SYSTEMATIC REVIEW OF RISK FACTORS ASSOCIATED WITH INCREASED EMERGENCY DEPARTMENT UTILIZATION IN

PATIENTS WITH SICKLE CELL DISEASE IN THE UNITED STATES

Authors: Samir K. Ballas,1 Carlton Dampier

2

Affiliations: 1Thomas Jefferson University,

Philadelphia, PA, USA; 2Emory University School of

Medicine, Atlanta, GA, USA

Background: Sickle cell disease (SCD) is a genetic

disorder that affects up to 100,000 patients in the

United States and affects multiple organ systems. The

emergency department (ED) is frequently used by

patients with SCD who have severe pain from vaso-

occlusive crises. The goal of this systematic review is to

identify predictors for ED use among patients with SCD

in the United States.

Methods: This systematic review was carried out using

the Preferred Reporting Items for Systematic Reviews

and Meta-Analyses (PRISMA) guidelines. PubMed and

Embase were searched for articles containing the

keywords “sickle cell disease” AND (“emergency” OR

“acute care”) AND (“utilization” OR “health care”)

published between January 1, 2000 and December 14,

2018. Included studies met the following inclusion

criteria: report of ED or acute care clinic use; report of

health care utilization for SCD; and report of ED visits

independent of hospital admission, ED revisits,

inpatient care visits, and SCD care unit visits. Articles

that were unavailable in English or focused on

populations outside of the United States were

excluded.

Results: Of the 23 articles included in the review

(Figure 1), 4 were prospective, and the remainder

were retrospective. Qualitative analysis of the articles

revealed a few trends, such as a higher rate of ED

utilization among adults relative to children, patients

with public insurance relative to private insurance, and

patients with more comorbidities, complications, or

pain. In one study, ambient temperatures less than

32°F were positively and clinically significantly

correlated with ED visits. Overall, gender was not

significantly associated with ED usage in most studies.

Conclusions: Age and pain levels were both commonly

cited as predictors of ED utilization. Findings from this

review highlight the urgent need for prospective

evaluations of predictors of ED utilization, as well as

assessments of psychosocial issues among patients

with SCD that may contribute to greater ED utilization.

Figure 1. Selection of Studies Evaluating Predictors for Emergency Department Utilization Among Patients With SCD

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JSCDH-D-19-00035

MAPPING AND IMMUNOLOGICAL PROFILING OF RED BLOOD CELL ALLOIMMUNIZATION AS A GENETIC TRAIT

IN ADULTS WITH SICKLE CELL DISEASE

Authors: Victoria R. Brooks

1,2, Sofia M.

LeMaire1, Fayuan Wen

2, Gulriz Kurban

2, James

G. Taylor VI2

Affiliations: Howard University Department of

Microbiology, Washington DC1.; Howard

University Center for Sickle Cell Disease,

Washington DC.2

Background: One of the primary treatments for sickle cell disease (SCD) is red cell transfusion. Its major limiting complication is alloimmunization to minor blood group antigens. Alloimmunization is rare in the general population,

but common in SCD. The underlying mechanism

has not been elucidated, but it is proposed that

susceptibility is a genetic trait. We hypothesized

that the biologic basis for this phenomenon may

involve population differences and that admixture

mapping could identify susceptibility loci.

Methods A cohort of 721 SCD adults had allo-antibody

status confirmed with the blood bank. Genomic

DNA was genotyped for a panel of 1622 ancestry

informative SNPs in 359 subjects. Ancestry was

estimated from these genetic data assuming an

admixture model for 3 ancestral populations.

Regression analysis was used to identify variables

associated with alloimmunization. Genome wide

admixture mapping was performed using a log-

additive case control study to identify regions of

the genome where ancestry differences between

cases and controls suggested an association.

Results

Seventy seven percent of the cohort had a

transfusion history with 153 (27.6 %) with allo-

antibodies and 65 (11.7 %) with no prior

transfusions. Univariate regressions showed

association lifetime transfusion history (logistic

regression by antibody status, β=0.56, P=6.31 x 10-

6). Amerindian ancestry was also associated with

alloimmunization (β=4.60, P=0.03), while African

and European ancestry were not. These

associations remained significant in a multivariable

model for alloimmunization status (P=0.09).

Genome wide mapping by admixture linkage

disequilibrium compared 91 cases to 210 controls

with prior transfusions under 10 different risk

models (range 0.25-9.0). The 0.25 risk model

showed a significant association (genome log factor

10.96, P<0.001). This scan identified a region of

chromosome 5 (5q21.3-5q31.1) defined by 14 snps

spanning 21.685 Mb with a peak LOD score of 13.5.

This region contains 209 genes and 4 microRNAs,

which are implicated in regulating hematopoiesis

and immune responses by Genomic Regions

Enrichment of Annotations Tool (GREAT) analysis.

Conclusion

Association with Amerindian ancestry suggested

admixture mapping is a suitable investigative

approach. Genome wide admixture mapping

identified a strong association at chromosome

5q21.3-5q31.1. Pathway analysis of this region

further suggests involvement in hematopoiesis and

the immune response. Ongoing analysis aims to use

immunological and gene expression profiling to fine

map allo-immunization susceptibility variants within

specific genes that underlies this association.

Ultimately, mechanistic knowledge of the immune

response directed towards minor blood group

antigens could lead to potentially novel strategies to

disrupt this process.

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JSCDH-D-19-00037 SYSTEMIC AND BONE TISSUE IMPACT OF L-GLUTAMINE THERAPY IN SICKLE MOUSE MODEL"

Author: Mykel Green, Mitchell Schaffler, Ph.D Gilda Barabino, Ph.D

Affiliation: City College of New York

Background: FDA approval of L-Glutamine (GLN) for patients with sickle cell disease (SCD) is a welcomed advancement, however opposing research has led to uncertainty about it’s therapeutic mechanism and long term safety. GLN is vital throughout the body and the benefit experienced by sickle patients may be explained by other means. Sickle bone, which progressively deteriorates with age, may benefit from GLN supplementation due its potential role as an anabolic agent. We aim to determine whether the Townes mouse model recapitulates the clinical observations of GLN therapy and assess tissue level implications via bone quality metrics.

Methods: Sickle mice and littermate controls were evaluated at 4-, 8-, 12-, and 16-weeks of age. GLN supplementation was given ad libitum via drinking water (1g/kg) from weaning (4-weeks) until time of sacrifice. Systemic assessment included plasma GLN concentration, NADH redox potential, lactate dehydrogenase (LDH) activity, hemopexin (HPX), and organ weights. Tissue analysis consisted of femur microCT examination of cortical and trabecular bone morphologies, and microarray of genes related to normal bone physiology.

Results: Plasma GLN of treated mice steadily increased to being higher than untreated (25%) and controls

(60%) at 16-weeks. Redox potential of GLN treated mice were significantly higher than untreated groups. LDH activity decreases by 25% in GLN mice at 8-weeks, but returns to untreated levels by 12-weeks. The concentration of HPX in GLN treated sickle mice is comparable to the untreated group at 8-weeks, but becomes significantly higher at 12- and 16-weeks. Organ masses revealed that GLN therapy hinders sickle splenomegaly from 4- to 8-weeks. The 12- and 16-week old time points showed two subgroups in GLN therapy: untreated resembling large spleens (<6% body mass) and wild-type resembling small spleens (<1% body mass). GLN treated mice with small spleens maintained nearly 40% more cortical and trabecular bone, while the large spleen subgroup returned an untreated phenotype by 16-weeks. Gene expression studies showed GLN therapy maintains relatively normal expression levels but significantly decreases FGF23 (~80%) at 8-weeks.

Conclusion: Mouse model recapitulates the reported clinical observations of GLN treated sickle patients, and serves as a viable model to investigate its role in SCD. Subsequent work will discern the inconsistent responsiveness to GLN therapy. Nonetheless, the reduction of organ weights and hemolysis markers suggests GLN supplementation may delay sickle vascular complications. Bone analysis supports GLN therapy maintains healthy tissue as well as highlighting sickle kidney pathophysiology as a pathway of interest.

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JSCDH-D-19-00038 STUDY OF EVALUATION OF THE NATIONAL POLICY OF COMPREHENSIVE ATTENTION TO PERSONS WITH SICKLE CELL

DISEASE AND OTHER HEMOGLOBINOPATHIES IN THE STATE OF BAHIA

Authors: Madlene Oliveira Souza, Silvone Santa

Barbara Silva, Evanilda Souza de Santana Caravalho

Affiliation: Universidad Estadual de Feira de Santana

Sickle cell disease is prevalent among the black

population and one of the priorities of this social

segment in the health policy struggle. In 2005, Brazil

instituted the National Policy for Comprehensive Care

for Persons with Sickle Cell Disease and Other

Hemoglobinopathies (PNAIPDF), estimating the annual

occurrence of 3,500 new cases of sickle cell disease

and 200,000 people with sickle cell trait. In addition,

the state of Bahia, constituted ethnically by blacks

(76.26%), has the highest incidence of live births with

sickle cell disease (1: 627) and sickle cell trait (1:17) in

Brazil. Bahia encompasses a strong social movement

and researchers in the search for improvements to

people with this aggravation, as well as the support of

affirmative policies. However, there are difficulties

such as the access of multiprofessional care and the

decentralization of specialized services, in which there

are only 9 Reference Centers out of 417 municipalities

in Bahia. In this sense, the present study aims to verify

to what extent the PNAIPDF and other

hemoglobinopathies in the state of Bahia can be

evaluated. This is an evaluation study of the PNAIPDF

with a descriptive and exploratory design, preceding

the ex-post evaluation studies of the implantation

analysis. The study is organized in three moments that

proposes the construction of the logical model, the

elaboration of the matrix of analysis and judgment and

the validation of the same one. For this, the

construction of the indicators plan will follow the

dimensions of access to health, management and

teaching and research actions and services for

PNAIPDF. In this way, the evaluation of health policy

aims to contribute to identify limits and possibilities,

with greater resolution to services, programs and

health systems, as well as elements that help the use

of new strategies and decision making, in order to

understand the possible significant variables of policy

implementation.

Key words: Sickle cell disease, Hemoglobinopathies,

Politicy.

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JSCDH-D-19-00039 A SECOND LOOK: A CASE OF ORBITAL MANIFESTATION IN SICKLE CELL DISEASE

Authors: Rebecca Berger, APRN1, Marisol Betensky,

MD1,2

, Kevin Potthast, MD3, E. Leila Jerome Clay, MD,

MCTS1,2

Affiliations: 1

Cancer and Blood Disorders Institute,

Johns Hopkins All Children’s Hospital, 2

Division of

Hematology, Department of Pediatrics, Johns Hopkins

University, 3Radiology Department, Johns Hopkins All

Children’s Hospital

Background: Sickle cell disease (SCD) is the most

common genetic disorder worldwide. Intra-ocular

involvement in sickle cell disease is a well-documented

clinical presentation though not often discussed by

hematologists. Orbital bone infarction in SCD is less

well defined1,2,3

. Prompt diagnosis is required to

prevent vision loss1. In this report we have a case of a

31 month old female with SCD (hemoglobin SS),

presenting with bilateral, symmetric infarctions of the

lateral periorbital regions, with sub-periosteal

hemorrhage.

Methods: A toddler with hemoglobin SS sickle cell

disease, maintained on hydroxyurea, with no previous

hospitalizations presented to a local emergency room

(ER) with a one-week history of bilateral eye swelling,

nasal discharge, malaise, and low-grade temperatures.

She was diagnosed with sinusitis and was started on

high dose amoxicillin. As the swelling worsened with

increased fevers, she returned to the local ER, which

prompted blood cultures and initiation of antibiotics

and orbital CT scan (Figure1). She was transferred to

our hospital for further care and began treatment with

Unasyn and Vancomycin. The patient was managed by

our team in conjunction with Infectious Disease,

ophthalmology and ENT consultations.

Results: Literature review was performed which

identified 4 articles with a total of 8 patients with

orbital infarction due to SCD with even one with

concurrent epidural hematoma4. All patients were

treated conservatively, with combinations of IV fluids,

simple transfusion, exchange transfusion, IV

dexamethasone, and IV antibiotics with full

recovery1,2,3

.

As our patient’s course improved with negative blood,

nasal cultures, respiratory pathogen panel and no

visual deficits, she was transitioned to oral Clindamycin

and Cefdinir on day 3. Additionally, her care was

managed with IV hydration, pain medications and

antipyretics. Bilateral temporal ultrasound was

obtained subsequently (Figure 2). Due to improvement

in the patient’s clinical course, and the need for

sedation, MRI was not obtained. Once improved

symptomatically, she was discharged to complete 14

day course of antibiotics while optimizing her dosing in

Hydroxyurea and with close follow up.

Conclusion: Given the unusual presentation, as sickle

cell providers, we often need to review the

presentation of orbital involvement in SCD aside from

retinopathy. Orbital involvement of sickle cell disease

is a rare occurrence, requiring rapid diagnosis for

accurate treatment to avoid long term sequela. There

is still more to be understood regarding adequate

management for such patients, severity of disease

prediction and the role of current disease modifying

agents like Hydroxyurea.

References

1. Alghamadi, A. Recurrent orbital bone sub-

periosteal hematoma in sickle cell disease: a

case report. BMC Ophthalmology. 2018; 18

(211). doi:10.1186/s12886-018-0884-1

2. Ganesh A, William RR, Mitra S, et al. Orbital

involvement in sickle cell disease: A report of

five cases and review literature. Eye.

2001;15(6):774-780.

doi:10.1038/eye.2001.248.

3. Huckfeldt RM, Shah AS. Sterile subperiosteal

fluid collections accompanying orbital wall

infarction in sickle-cell disease. Journal of

American Association for Pediatric

Ophthalmology and Strabismus.

2014;18(5):485-487.

doi:10.1016/j.jaapos.2014.04.004.

4. Naran AD, Fontana L. Sickle cell disease with

orbital infarction and epidural hematoma.

Pediatric Radiology. 2001;31(4):257-259.

doi:10.1007/s002470000406.

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Figure 1: CT scan. Left image showing bilateral orbital and temporal hemorrhages. Right image showing

temporal fluid collection, greater on left.

Figure 2: Ultrasound: Right temporal sub-periosteal hematoma

L

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JSCDH-D-19-00050 BENEFITS OF A COORDINATED TRANSFUSION MEDICINE AND HEMATOLOGY

SICKLE CELL DISEASE QUALITY PROGRAM Authors: Iram Puthawala, Grifty Menka, RN, Dre

Miller, MHA, Valerie Mann-Jiles, APRN-CNP, Amanda

Hrnicek, MBA, Kimberly Weirick, NDP, Scott Scrape,

MD, Eric Kraut, MD, Payal Desai, MD

Affiliation: Ohio State University Wexner Medical

Center

Background: Red cell exchange (RCE) is a mainstay of

treatment of sickle cell disease (SCD) complications.

Compared to simple transfusions, exchanges have the

benefit of decreasing iron overload. Indications for

chronic RCEs include secondary prevention of stroke,

prevention of future episodes of Acute Chest

Syndrome if already on hydroxyurea, refractory pain

despite hydroxyurea, persistent stuttering priapism,

and pulmonary hypertension. Given the multiple

indications for transfusions in SCD patients, we sought

to have a collaborative quality program to establish

standards of care and improve adherence to RCEs.

Methods: In 2016, hematology and transfusion

medicine at the OSUCCC—James began a combined

quality program in which they reviewed SCD patients

quarterly. During these meetings, patients were

reviewed to ensure they were undergoing evidence-

based treatments and psychosocial barriers to RCE

were addressed. We sought to evaluate the impact of

the program on patient outcomes.

Results:

Year

Number of patients on chronic exchange

Male (total)

Female (total)

Inpatient and outpatient exchanges (average, per patient)

RBC units exchanged (average, per patient)

Outpatient exchanges (average, per patient)

Percent of patients receiving ≥4 outpatient exchanges per year

Inpatient exchanges (average, per patient)

Inpatient admissions (average, per patient) Mortality

Average ferritin

2014 6 5 1 6.17 44.33 4.33 66.67 1.83 9 0% 1663.75

2015 6 6 0 5 38.17 3.33 33.33 1.67 5.33 0% 3652.44

2016 10 8 2 5.1 39.8 4.4 60 0.7 3.2 0% 2735.04

2017 18 9 9 6.45 48.89 4.89 61.11 1.56 5.06 5.55% 1650.1

2018 20 9 11 7.2 53.85 5.4 70 1.7 5.2 0% 1980.44

107 unique patients with SCD underwent RCE during

this time. Data regarding 27 patients who were on

chronic RCEs was analyzed. In total, the patients on

chronic exchanges underwent 378 RCEs, of which 286

were outpatient.

Conclusions: Since the quality program began in 2016,

the average number of total (inpatient/outpatient) and

outpatient exchanges increased. Furthermore, the

total number of patients on chronic exchanges as well

as the percentage of patients who underwent at least

4 outpatient exchanges per year increased yearly since

2016. While currently we did not see a decrease in the

number of inpatient exchanges, there is likely a false

elevation caused by patients who undergo non-

emergent exchanges when admitted for convenience.

Closer monitoring also led to an overall downtrend in

ferritin levels. We conclude that a structured quality

program between hematology and transfusion

medicine leads to improved care for patients with SCD

on chronic transfusions.

0

5

10

2014 2015 2016 2017 2018

Average number of transfusion exchanges, per patient

Total Outpatient Inpatient

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JSCDH-D-19-00051 IT IS NOT JUST ABOUT THE OPIOID PRESCRIPTION: THE PATIENT PERSPECTIVE ON

THE USE OF OPIOIDS TO MANAGE SCD PAIN.

Authors: Cynthia Sinha, Diana Ross, Nitya Bakshi, Faud El Rassi, Lakshmanan Krishnamurti

Affiliation: Emory University

Background: The hallmark of SCD is vaso-occlusive pain, which may be acute and episodic but may progress to chronic persistent pain with unpredictable and disabling exacerbations. Gaps in practice in the management of SCD related pain are well established with little data regarding the patient perspective on opioids and their use in the management of SCD related pain. This qualitative study sought to understand the perspective of the adult patient with SCD in the use of opioids in the management of SCD related pain.

Methods: We conducted qualitative interviews of adult SCD patients from a geographically diverse population recruited from national conferences and local clinics. A semi-structured open-ended interview guide was used to collect data. Audio recordings were transcribed verbatim. Transcripts were coded using descriptive qualitative analysis using NVivo 11.

Results: We interviewed 26 adults (19 females) all African American of age ranging from 21 to 52 years old, ten employed full-time or part-time and 16 receiving social security disability benefits. All participants self-reported that their genotype was either HbSS, HbSC, and or HbS-Beta thalassemia. Participants were interviewed in-person and over phone. All participants reported pain on three or more days a week and had a current prescription for opioids to treat their pain. We developed three themes to address our research objective.

“You know, we’re just hurting and we’re trying to get people to hear us.” First, participants felt physicians only focus on prescribing opioids and do not try to evaluate the underlying cause of pain. Patients want to feel listened to and included in the discussion of understanding their pain.

“It eases the pain, it doesn’t take it away.” Second, participants reported they prefer not to rely on opioid therapy to manage their acute and chronic pain as opioids only temporarily ease their pain without eliminating the cause of the pain.

“Granted it helped but now what?” Third, participants are concerned about the adverse side effects of long-

term opioid therapy, and are worried about becoming physically dependent on opioids.

Conclusion: Adult SCD patients would like their physicians to focus on evaluation of underlying causes of pain in discussion with them rather than merely focus on prescribing opioids. Patients are dissatisfied with opioids which they see as temporary fix to their problem and are worried about adverse effects and physical dependence.

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JSCDH-D-19-00052 GAZELLE: A PORTABLE, AFFORDABLE POINT-OF-CARE DIAGNOSTIC TECHNOLOGY

FOR DETECTING HAEMOGLOBIN DISORDERS IN INDIA

Authors: Kumar R1, Shrivas S1, Verma AK1, Thota P2, Bharti

PK1, Rocheleau A2, Witte T2, Uikey R1, Hasan MN3, Gurkan

UA3, Rajasubramaniam S1

Affiliations: 1Indian Council of Medical Research (ICMR)-National Institute of Research in Tribal Health, Jabalpur, India 2Hemex Health, Portland, OR, 3Case Western Reserve

University, Cleveland, OH

Background: Sickle haemoglobin (HbS) and thalassaemias are the most common inherited disorders of blood resulting in anaemia and associated complications. Sickle Cell Disease (SCD) is particularly common among natives of sub-Saharan Africa, India and Mediterranean countries. Screening in India involves solubility and sickling slide test followed by confirmation by High-performance liquid chromatography (HPLC) or haemoglobin electrophoresis. Lack of public health diagnostic facilities contribute to vast majority of

hitherto undetected patients resulting in increased morbidity and mortality. Here, we describe the field performance of microchip based cellulose acetate electrophoresis “Gazelle

TM”. The study was conducted in

tribal-dominated Madhya Pradesh and Chhattisgarhstates in India, regions where HbS prevalence varies from 3% to 35%. Gazelle

TM is a rapid (<10 minutes) and easy-to-use test

which can be performed by minimally trained personnel using only a finger-prick volume of blood.

Methods: Blood samples were collected from 300 patients who were enrolled in a pilot study in a high prevalence setting (ICMR-NIRTH, India). Each sample was tested with Gazelle

TM, and the results were

compared to electrophoresis and HPLC. Overall, 295 patient samples were included in the analysis (3 samples were excluded due to incomplete runs; sequencing results pending for 2 samples).

Results: Gazelle yielded a high accuracy (100%) compared to standard laboratory tests (Table 1).

Table 1. Overall accuracy of Gazelle in comparison to clinical standard tests.

Category Hemoglobin Type Correct Incorrect Accuracy

Sickle Cell Disease and sickle

β-Thalassemia

HbSS, HbSβ-thal 12 0 100%

Sickle Cell Trait HbAS 62 0 100%

Normal HbAA 221 0 100%

All categories - 295 0 100%

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GazelleTM

demonstrated high sensitivity and high specificity for identifying SCD (HbSS) and β- Thalassemia, sickle cell trait (HbAS)

(Table 2).

Table 2. Sensitivity and specificity of Gazelle in comparison to clinical standard tests.

Category True

Positive

True

Negative

False

Positive

False

Negative

Sensitivity Specificity PPV NPV

Sickle Cell Disease

HbSS/HbSβ- thal vs.

HbAA

12 221 0 0 100 100 100 100

Sickle Cell Disease

HbSS/HbSβ- thal vs.

HbAS

12 62 0 0 100 100 100 100

Sickle Cell Trait HbAS

vs.

HbAA

62 221 0 0 100 100 100 100

Conclusions: Microchip electrophoresis technology

offers a low-cost ($2 per test), rapid, and accurate

method for detecting hemoglobin disorders such as

SCD. Gazelle can be a potential clinical tool for rapid

diagnosis of SCD and other hemoglobin disorders in

resource-limited settings.

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JSCDH-D-19-00065 TIME-TREND OF MORTALITY OF BLACK WOMEN AND MEN BY SICKLE CELL DISEASE IN THE STATES OF BAHIA - BRAZIL, NORTH

CAROLINA AND SOUTH CAROLINA - UNITED STATES, 1999-2016. Authors: Aline Silva Gomes – Universidade Estadual de Feira de Santana – Brasil, José Roberto Santos Silva – Universidade Federal da Bahia – Brasil, Carlos Alberto Lima da Silva - Universidade Estadual de Feira de Santana – Brasil, Evanilda S. de Santana Carvalho - Universidade Estadual de Feira de Santana – Brasil, Coretta Melissa Jenerette – University of North Carolina and University of South Carolina – Estados Unidos, Abbas Tavakoli - University of South Carolina – Estados Unidos

OBJECTIVE: To analyze the time-trend of mortality of black men and women from sickle cell disease (SCD) in the states of Bahia - Brazil, North Carolina and South Carolina - United States, from 1999 to 2016. METHODS: Ecological study of time series that considered the deaths due to SCD of black women and men (ICD 11-D57), residing in the states of Bahia, North Carolina and South Carolina, from 1999 to 2016. The data from the state of Bahia were accessed at the Department of Information System of the Unified Health System in November 2018, and the data from the US states were obtained through the Platform for Disease Control and Prevention in December 2018. The Trend

of mortality rates by SCD was analyzed by the adjusted regression model of Prais-Winsten, (Rate)t = α + β (time)t + ϵt (95% confidence interval), to compile data, we used the Microsoft program, Office Excel 2010, and to analyze the trends we adopted the statistical program R, version 3.5.0.

RESULTS: We observed a growing trend in the mortality rate of black women and men by SCD in Bahia, with emphasis on the ages 0-9 and 10-19. In South Carolina, we observed a decreasing trend in the age group 10 to 19 years, while in the state of North Carolina, there is a steady trend of mortality among black women and men in all age groups. CONCLUSION: This study highlights the need for priority actions for the health of children and teenagers with SCD in the Brazilian state. We recommend to know the successful experiences of the State of North Carolina seeking to overcome the limitations to reduce mortality due to SCD in the state with increasing tendency of mortality due to SCD.

Keywords: Mortality; Mortality Registries, Sickle Cell disease; Epidemiology; Time Series Studies

Table 1: Results of the trend analysis of the mortality rates series by sickle cell disease, by State, women and black men and age group, 1999-2016.

Variável Beta t-valor p-valor Tendência

ESTADOS

Total - BA 0,02 7,83 <0,001 Crescente

Total- NC -0,0039 -1,88 0,078 Estável

Total - SC 0,0004 0,1 0,921 Estável

SEXO/NÃO BRANCOS

Homem - BA 0,024 7,968 <0,001 Crescente

Homem - NC -0,0172 -1,323 0,204 Estável

Homem - SC -0,012 -0,523 0,608 Estável

Mulher - BA 0,023 6,429 <0,001 Crescente

Mulher - NC -0,015 -1,345 0,198 Estável

Mulher - SC 0,017 1,138 0,272 Estável

GRUPO ETÁRIO

1 a 9 - BA 0,014 2,696 <0,01 Crescente

1 a 9 - NC -0,003 -0,004 0,501 Estável

1 a 9 - SC 0,0007 0,106 0,917 Estável

10 a 19 - BA 0,015 3,526 <0,001 Crescente

10 a 19 - NC 0,00088 0,003 0,795 Estável

10 a 19 - SC -0,015 -2,148 <0,05 Decrescente

20 a 64 - BA 0,031 7,627 <0,001 Crescente

20 a 64 - NC -0,0082 0,0042 -1,96 Estável

20 a 64 - SC 0,005 0,821 0,424 Estável

65+ - BA 0,006 1,082 0,295 Estável

65+ - NC 0,0018 0,795 0,438 Estável

65+ - SC 0,0007 0,118 0,908 Estável

Tabela 2. Resultados da Análise de Tendência das séries de taxas de mortalidade, por Estados, Homens e

Mulheres Não Brancos e grupos etários.

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JSCDH-D-19-00066 SUPPRESSION OF HBF REPRESSORS BY SMALL MOLECULES AND RESPONSES IN DIFFERING SNP

PROFILES: POTENTIAL RELEVANCE FOR TAILORING GENE MODULATING THERAPIES

Authors: Yan Dai, Betty Pace, David Chui, S.P. Perrine

Affiliations: Phoenicia BioSciences Inc, Augusta University,

and Boston University School of Medicine

Background: Up-regulation of HbF in a majority of red blood

cells is clinically proven to reduce anemia and clinical severity

in sickle cell disease (SCD) and beta thalassemia (BT). More

than 70 small molecules induce fetal globin gene expression in

vitro, through diverse, potentially complimentary molecular

mechanisms with exposure during a specific period of EPO

sensitivity. Small molecule therapeutics can be pulsed or

given sequentially to promote efficacy, reduce off- target

effects on other lineages. Genetic modifiers relevant to

baseline HbF could influence the magnitude of induction by

targeted gene editing or small molecule therapeutics.

Methods: Three HDAC inhibitors, ST20 (which displaces

HDAC2), and a therapeutic with multiple actions, PB-04,

which displaces or suppresses transcriptional repressors

HDAC2 and HDAC3, LSD-1, and BCL11A were evaluated in

erythroid progenitors cultured from >100 sickle cell and

thalassemia patients. Fetal globin mRNA, F-reticulocytes, and

F protein/cell were assayed. ChIP assays and Western blots

were performed to assess drug effects on repressor

components. Comparative induction was preliminarily

assessed in the progenitors by SNPs related to basal HbF

levels or cell survival.

Results: All HDAC inhibitors and ST20 significantly reduced or abolished BCL11A protein in erythroid progenitors. Addition of PB-04 once during erythroid differentiation resulted in loss of BCL11A protein and reduced binding of BCL11A, LSD-1, and HDAC3 appeared at the same time. The relative fold-globin mRNA above untreated controls was highest (5-9 fold) in progenitors from patients with SNP profiles associated with lower baseline fetal globin levels in BCL11A (766432 and 1427407), ZBTB7A, OR51B4, Xmn-I (7482144) and rs 4601817. Induction was 4 to 9-fold in progenitors from GG and GA patterns in AKAP12, (rs10872670 associated with cell senescence) and G/G in SNX29P2 (rs 1872670), but was 1.3- to 3-fold in other SNP profiles. Conclusions: Multiple HbF inducers suppress LSD-1 and BCL11A protein binding to the promoter. Responses in erythroid progenitors with differing SNP profiles suggest that genetic modifiers relevant to baseline HbF or F-cells may offer a means to guide modulating therapies.

Figure 1. Western blot and ChIP assays show loss of BCL11A, LSD-1 and new histone activation marks with PB-04

exposure in erythroid progenitors.

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FEATURED MANUSCRIPT

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JSCDH-D-18-00076R1 THE PATTERN OF BLOOD PRESSURE AND RENAL FUNCTION AMONG CHILDREN WITH SICKLE CELL ANAEMIA PRESENTING IN A

TERTIARY HEALTH INSTITUTION IN NIGERIA.

Type of Manuscript: A cross-sectional study (original research) Authors: Adebukola Ajite

1, Ezra Ogundare

1, Oludare Oluwayemi

1, Oladele Olatunya

1 , Oluwasola Oke

1, Kayode Tolorunju

2,Evelyn

Omoniyi1,

Affiliations:

1Department of Pediatrics, Ekiti State University Teaching Hospital, Ado Ekiti.

2Department of Chemical pathology, Ekiti

State Teaching Hospital, Ado Ekiti Corresponding Author Dr Adebukola Ajite Department of Paediatrics, Ekiti state university teaching hospital, PMB 5355, Ado Ekiti Email : bidemi_kayode@yahoo.com Tel +2348069712558

ABSTRACT

Background: In sickle cell anemia (SCA), compromise of the renal vasculature due to sickled red cells has been recognized.

Objectives: To assess the renal function and blood pressure pattern in children with sickle cell anemia (SCA) presenting in a tertiary

institution

Method: A cross-sectional study of patients with sickle cell anemia (SCA) over six months involving the use of questionnaires,

general physical examination, blood pressure, investigations for hemoglobin genotype, urinalysis, serum creatinine, screening for

hepatitis B and HIV.

Results: 51 children with SCA were seen. The prevalence of impaired renal function as defined by reduced eGFR <90mL/min/1.73m2

in this study was 27.5%, previous hospital admission and blood transfusion were associated with reduction in eGFR but blood

pressure did not have significant correlation with the eGFR. The overall mean age at diagnosis of SCA was 4.09 ± 3.33 (years).

Conclusion: Impaired renal function is a major comorbid condition in children with SCA. In countries/locations where there is no

newborn screening for sickle cell disease, diagnosis is delayed, thus detecting impaired renal function may be delayed, therefore the

need for early detection and management is imperative.

Introduction: Sickle cell disease (SCD) is a clinical condition in which an individual inherits two abnormal hemoglobin (Hb) genes following mutation and at least one of which is Hemoglobin S (HbS)

1. HbS is the result of a single base pair

change, thymine for adenine, at the 6th codon of the β-globin gene

1. This change encodes valine instead of glutamine in the

6th position1, 2

. Consequently, there is production of an unstable isoform which when slowly deoxygenated can polymerize leading to the production of sickle cell

3. The most

severe type is HbSS, otherwise called sickle cell anemia (SCA) which occurs when both β-globin genes have the sickle cell

mutation 1,2

. Sickle cells lack the fluidity of the normal erythrocytes and can impede capillary flow thereby leading to

tissue ischaemia3,4

. The kidney, being a highly vascular organ, is vulnerable to vaso-occlusive events. The hemodynamic changes that occur with chronic anemia, renal hypoxia from recurrent vaso-occlusion and hemolysis-related endothelial dysfunction can lead to functional and structural changes presenting as hematuria, proteinuria, concentrating defect, renal insufficiency and hypertension which may progress to chronic kidney disease (CKD)

5-8.

Renal disease in patients with sickle cell anemia is a major comorbid condition that is seen in 15-18 % of all SCD patients, and is a cause of early death

5, 9. The presence of renal failure

in sickle cell disease (SCD) ranges from 5 to 18% of the total population of SCD patients

9.

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Blood pressure has been found to be lower in SCD patients when compared with their healthy counterparts with normal hemoglobin genotype and this has been attributed to the low systemic vascular resistance seen in them

10-15. For the same

reason, hypertension is uncommon in sickle cell disease patient, hypertension in them predisposes to greater risk of vaso-occlusive crisis and death

16. Compromise of the renal

vasculature due to sickled red cells has been associated with glomerular hypertrophy, glomerular hyperfiltration and consequent proteinuria

16. Hemolysis in SCA may also

contribute to the development of kidney disease due to the increase in levels of plasma free hemoglobin and subsequent hemoglobinuria. The free heme filtered through the glomerulus is directly cytotoxic to renal tubular epithelial cells and induces damaging inflammatory responses

17.

Objectives: This study was conducted to contribute to existing data on the pattern of blood pressure and renal function among children with sickle cell anemia.

Study design and location: A cross-sectional study of patients diagnosed to have sickle cell anemia who were attending the pediatric hematology clinic of Ekiti State University Teaching Hospital Ado Ekiti was done over a period of six months from June 2016 to December 2016 after obtaining an ethical clearance from the Ethical and research committee of the institution.

Data collection and sampling technique: Patients presenting at the pediatric hematology clinic during the duration of the study (six months) were serially recruited provided they met the inclusion criteria and after obtaining informed parental consent as well as assent from the patients, where applicable. Inclusion criteria included patients aged two to sixteen years who were diagnosed by hemoglobin electrophoresis to have sickle cell anemia and presenting at the pediatric hematology clinic over a period of six months. Exclusion criteria included patients who had crises or were admitted at least two weeks prior to their scheduled clinic visit, patients on blood pressure lowering medication and those on steroids. Questionnaires were administered to consenting parents and subjects. Information requested for included the age, gender, age at diagnosis, regularity of clinic attendance, compliance with routine medication, number of hospital admissions in a year, common crisis noticed and previous blood transfusion. General physical examination, weight, height and blood pressure of the subjects were done alongside investigations such as hemoglobin genotype, urinalysis, serum creatinine , hepatitis B and HIV screening.

Blood pressure measurement: Blood pressure was determined using standard procedure according to the recommendation of the task force on high blood pressure in children and adolescent

17. This was done by auscultation in

the right arm after a 10-minute resting period using the mercury gravity sphygmomanometer with appropriate

bladder cuff sizes. The onset of the first tapping sound (Korotkoff sound 1) was taken to indicate the systolic blood pressure (SBP) while the point of complete disappearance of the sound (Korotkoff sound 5) was taken to indicate the diastolic blood pressure (DBP). For each subject two measurements were taken after an initial blood pressure trial run to achieve subject’s confidence and composure. The average reading was then determined

18.

Urinalysis: Freshly voided urine was collected from every subject into a plain universal bottle and the UriScreen Combi 10 dipstick was used to assess urine protein semi-quantitatively, specific gravity of the urine as well as the presence of erythrocyte were also assessed. The test strip was dipped into the freshly voided urine for approximately 1 second, and then drawn across the edge of the container to remove the excess urine. After 30 seconds, the test strip was compared with the colour scale and the result was recorded immediately. Colour changes taking place after 2 minutes was regarded as of no significance. The amount of protein in the urine was assessed as negative, trace, 1+ (30 mg /dL), 2+ (100 mg/ dL), 3+ (500 mg/dL).

Patients with proteinuria had repeat urinalysis on three consecutive occasions over three months to ascertain those at risk of chronic kidney disease.

Estimated glomerular filtration rate: This was calculated by using the Schwartz formula

19, where the estimated

glomerular filtration rate = kh/ serum creatinine in mg/dl (k is a constant 0.55 in children and adolescent girls and 0.77 in adolescent male, h is the height in cm) and serum creatinine was assessed using modified Jaffe’s method, type is endpoint, wavelength 520nm and the instrument is Spectioscan 60 DV, Biotech Engineering co.uk

Data analysis: Data analysis was performed using both descriptive and comparative statistics. Descriptive statistics comprising of mean, standard deviation, percentages and proportions were used for the age, anthropometry, estimated glomerular filtration rate and blood pressure profile of the subjects.

The comparative statistics comprised of Chi-square test for categorical data, independent samples t-test and analysis of variance (ANOVA) for comparison of the mean of continuous dependent variables for categorical variables with three or more categories. Pearson’s correlation was also done

RESULTS: Fifty one children with sickle cell anaemia were studied over a period of six months with the age range of two to sixteen years. Thirty nine (76.5%) of them were male while twelve (23.5%) of them were female. All the subjects had homozygous haemoglobin SS. Serology test for hepatitis B, C and HIV were negative in all of them.

91 | P a g e

THE BIODATA AND ANTHROPOMETRIC CHARACTERISTICS OF THE SUBJECTS

Age and sex distribution: The male to female ratio was 3.25:1 Out of the 51 subjects, 19 (37.3%) were aged 2-5years, 16 (84.2%) of them were males and 3 (15.8%) were females. Those aged 6-9years were 13 (25.5%), 10 (76.9%) of them were males and 3 (23.1%) were females. Those whose ages were ≥ 10 years were 19 (37.2%) and 13 (68.4%) of them were males and the remaining 6 (31.6%) were females.

Table I shows a comparison of the mean age at the time of the study, mean age at diagnosis of the disease condition, mean anthropometry and blood pressure profile based on the gender. There were no statistically significant differences in these parameters between genders. The overall mean age at diagnosis was 4.09 ± 3.33 (years), however, the mean age at diagnosis was earlier in male as compared to female. The mean values for blood pressure, mean arterial pressure and estimated glomerular filtration rate were all within normal range for each gender and there were no statistically significant difference between them.

Parents level of formal education, clinic attendance and routine medication: Among the subjects, 37 (72.5%) of the fathers had at least tertiary level of education, while 33 (64.5%) of the mothers had same. Majority of the patients 35 (69%) attended hematology clinic regularly, at least once in two months, however, the teenagers rarely came for follow up. The routine medication used by these subjects included; folic acid, multivitamin and Proguanil.

Blood pressure percentiles: Among the male subjects the systolic blood pressure percentiles recorded were; less 50

th

percentile [21(53.8%)], 50th

percentile [2(5.1%)], >50th

percentile to <90th

percentile [13(33.3%)] and 90th

percentile [3(7.7%)]. The diastolic blood pressure percentile recorded were; <50

th percentile [19(48.7%)], 50

th percentile [2(5.1%)],

>50th

-<90th

percentile [17(43.6%)] and 90th

percentile [1(2.6%)]. Among the female subjects 10(83.3%) had the systolic blood pressure percentiles less than 50

th percentile

while 2(16.7%) had theirs between >50th

percentile to <90th

percentile. The diastolic blood pressure percentiles recorded were; <50

th percentile [9(75.0%)], 50

th percentile [2(16.7%)]

and >50th

percentile to <90th

percentile [1(8.3%)]. Majority of all the subjects had both diastolic and systolic blood pressure less than the 50

th percentile and none of the subjects had

blood pressure percentile above the 90th

percentile for age and gender.

Serum Creatinine and estimated glomerular filtration rate (eGFR): As seen in figure 1, the serum Creatinine levels were majorly less than 1mg/dl. The eGFR value for the subjects ranged from 32.2mL/min/1.73m

2 to 197.0mL/min/1.73m

2.

The mean eGFR for the subjects was 105.75±35.66. In figure

2, the eGFR for the male subjects were divided into classes of normal eGFR (90-120ml/min/1.73m

2), mildly reduced

eGFR(60-89 ml/min/1.73m2), moderately reduced eGFR (30-

59 ml/min/1.73m2), severely reduced eGFR (29-15

ml/min/1.73m2

), end stage kidney disease(<15 ml/min/1.73m

2), elevated eGFR (>120-139 ml/min/1.73m

2 )

and glomerular hyperfiltration (>140 ml/min/1.73m2

). Eight (20.5%) male subjects had mildly reduced eGFR while 5(12.8%) had moderately reduced eGFR.

Majority of the

female subjects had eGFR above 90 ml/min/1.73m

2 as seen in

figure 3, only one female subject had mildly reduced eGFR (60- 89mL/min/1.73m

2). The prevalence of reduced eGFR

(<90ml/min/1.73m2) among the study population was 27.5% (14 subjects). These patients with reduced glomerular filtration cut across age 2-13years; more than half of them had previous hospital admission and blood transfusion as seen in figure 4 and 5 respectively. None of the subjects had eGFR <15mL/min/1.73m

2. However, in Figure 6, all the

subjects with age ≥ 14 years had estimated glomerular filtration suggestive of glomerular hyperfiltration (eGFR ≥ 140mL/min/1.73m

2).

Proteinuria and haematuria: The prevalence of dipstick proteinuria among the subjects was 11.8% (6subjects), the proteinuria was in the range of 30mg/dl -100mg/dl. The age range of these subjects with persistent proteinuria was 2-13years and 4(67%) of them had previous blood transfusion and all were male. The eGFR range of subjects with proteinuria was 94.8-169.0mL/min/1.73m

2. Three of these

subjects had eGFR ≥ 140mL/min/1.73m2. One subject (12year

old male) had dipstick detected blood in the urine; the eGFR was also above 90mL/min/1.73m

2

Correlation of age at diagnosis, anthropometry, blood pressure and estimated glomerular filtration rate.

Using Pearson’s correlation, there was a significant positive correlation of the age at diagnosis of the disease condition with the height and the weight of the patients, the correlation was 0.678 and 0.536 respectively and both were significant at 0.01level with 99%degree of confidence. The estimated glomerular filtration rate was also shown to have a significant positive correlation with the weight and height, the correlation was 0.678 and 0.536 respectively and both were significant at 0.01level. Blood pressure parameters had no significant correlation with the estimated glomerular filtration rate.

DISCUSSION: In the study, there was a male preponderance with M:F of 3.25:1. The age range of the subjects was 2-16 years, it was noticed that the population of the subjects was like a pyramid with a decline in the population as the age increased. This could be explained by the increase in mortality and poor survival of children with haemoglobinopathy in resource poor setting

20 such as the

location of this study. The increase in mortality and poor survival may be attributed to ignorance of the disease

92 | P a g e

condition, poverty, environmental factors like the malaria endemicity and delay in presentation in the hospital. The overall mean of age of the subjects at first diagnosis was 4.09 ± 3.33 years which depicted delay in diagnosis when compared with developed countries with the facility for newborn screening. This also suggests that the haplotype of sickle cell in these patients may be of less severity, making the patients to present to the hospital with symptoms at older age since facility for newborn screening is not widely available yet. There is also the possibility that the most severe cases had died before presenting at the hospital for routine care. The blood pressure pattern showed that both systolic and diastolic blood pressure were below 50

th percentile for most

of the patients across genders. This is in agreement with the documentation of low blood pressure in sickle cell disease patients which has been attributed to low systemic vascular resistance seen in them

3. The serum creatinine levels were

majorly less than 1mg/dl in the recruited subjects. Reduced muscle mass as compared with normal healthy individuals may be one of the contributing factors. Similar finding was reported in a study among adults with sickle cell disease

21.

The prevalence of dipstick positive proteinuria in this study was 11.8%, this is lower than the prevalence of 20.0% recorded in adult Nigerian patients with SCA by Aneke et al

22.

This disparity can be explained by the difference in the ages of the study population. Out of the six subjects with persistent proteinuria, 5(83.3%) of them were above the age of 5years, the tendency to have persistent proteinuria seemed to increase with age. Age has been described as the most potent modifying factor of sickle nephropathy of which persistent proteinuria is a feature and progression to overt CKD has been noticed in early adulthood

23.

In this study, the six patients with proteinuria had their eGFR in the range of 94.8-169.0mL/min/1.73m

2and half of them

had eGFR above 140ml/min/1.73m2

suggestive of glomerular hyperfiltration. A previous study

24 reported similar finding

that higher rates for developing microalbuminuria were seen in SCA patients with glomerular hyperfiltration and the same study also noted that the prevalence of hyperfiltration decreased with age

24. These subjects may be in the early

phase of kidney damage with compensatory increase in glomerular filtration which may be responsible for the enhanced glomerular passage of albumin and larger proteins that has been previously described in SCD

3. Age related

progression to chronic kidney disease and decrease in renal function may be implicated in the reduction of the prevalence of hyperfiltration with age as seen in the study of adults with SCA

21.

The prevalence of impaired renal function as defined by reduced estimated glomerular filtration rate <90mL/min/1.73m

2 in this study was 27.5%. The subjects

with reduced glomerular filtration rate cut across ages 2-13years and had at least an episode of previous hospital

admission and blood transfusion. This suggests that renal impairment is common in sickle cell anaemia and that sickle cell crisis which is severe enough to warrant hospital admission and blood transfusion may be a contributing factor. Ongoing hemolysis and vaso-occlusive injury have been reported to likely contribute to continuing renal injury

17, 23. Among patients with sickle cell disease, decreased

kidney function has been reported in 5 to 30 percent 21, 25, 26

which is close to our finding in this study. A higher prevalence of 67.6% was recorded by Yusuf et al

27 in his study

of adults with SCA in Zaria, Nigeria using similar cut off point of eGFR of <90 ml/min/1.73m

2. Previous scholars have

suggested that as more individuals with SCD are reaching the fourth to sixth decade of life, the prevalence and risk of CKD is likely to increase as well

23 , this may explain the higher

prevalence of decrease kidney function seen in adults with SCD.

The range of eGFR in normal children aged 2-12years was put at 89-165mL/min/1.73m

2 by Heilben et al

28 in 1991, however

in this study among children with sickle cell anaemia, the range was 32.2mL/min/1.73m

2 -197.0mL/min/1.73m

2.

Worthy of note is the fact that all subjects above the age of 14years had the estimated glomerular rate above 140ml/min/1.73m

2. An earlier study by Olowu et al

29 among

children with sickle cell disease patient aged 5-13years showed that Nigerian children with homozygous sickle cell anaemia who are in steady states have normal glomerular filtration rate while studies in adult SCD showed reduced glomerular filtration rate

19,20. The disparity in the outcome of

these various studies may be due to the fact that the changes in the glomerular filtration rate could be a spectrum; with the earlier ages 5-13years having predominantly normal glomerular filtration rate

23, ages > 14years having glomerular

hyperfiltration as a feature of compensation in early kidney disease as seen in this study and the adults SCD patients having reduced glomerular filtration rate due to age related renal decompensation

21, 25. A similar continuum of

hyposthenuria in children to progression to end-stage renal disease (ESRD) in adults has been described by other authors

23. Although in the early ages the eGFR values were

predominantly normal in this study, evidence of glomerular hyperfiltration as suggested by eGFR >140ml/min/1.73m

2 was

seen across all the ages from 2-16 years. Similarly, hyperfiltration has been seen as early as 9–19 months of age according to the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) study

30. The compromise of the renal

vasculature due to sickled red cells has been associated with glomerular hyperfiltration, proteinuria and glomerular hypertrophy. However, there is need for further elaborative study to unravel factors implicated in the outset of glomerular hyperfiltration in sickle cell anaemia.

There was no correlation between the estimated glomerular filtration rate and the blood pressure of the subjects in this study; this is similar to previous observation that in contrast to other glomerulopathies, the development of systemic

93 | P a g e

hypertension is uncommon in HbSS subjects with renal insufficiency

21.

CONCLUSION: The prevalence of renal insufficiency as demonstrated by estimated glomerular filtration rate of <90mL/min/1.73m

2 was 27.5%. Previous hospital admission

and blood transfusion were associated with reduction in eGFR but blood pressure did not have significant correlation with the eGFR. There is delay in diagnosis of SCA and the prevalence of persistent proteinuria and glomerular hyperfiltration was noticed to increase with the age of the subjects. Therefore, there is a need for early detection and

management of SCD to forestall recurrent vasoocclusive crises and end organ (kidney) damage. However, in the absence of newborn screening for SCD in some countries/locations leading to delay in diagnosis, early detection of renal function is critical. Routinely, renal function in sickle cell disease patients should be monitored as some might actually have impaired renal function with a need to adjust dose of medication, ensure prompt intervention and follow up.

REFERENCES

1. Michael R. DeBaun Elliott Vichinsky. Hemoglobinopathies: Nelson Textbook of Pediatrics, RE Berman, RM Kliegman,HB Jenson,BF Stanton. 18th ed. Philadephia, 2007.

2. Adekile AD, Adeodu O. Hemoglobinopathies. Paediatrics and child health in tropical region. 2nd

ed 373-390.

3. Guasch A, Cua M, Mitch WE; Extent and course of glomerular injury in patients with sickle cell anaemia. Kidney Int 49:786-791, 1996.

4. Guasch A, Cua M, Mitch WE; Sickle cell anaemia causes a distinct pattern of glomerular dysfunction. Kidney International 51;826-833,1997.

5. Serjeant GR, Serjeant BE. Sickle Cell Disease, 3rd ed. edn. Oxford, United Kingdom: Oxford University Press; 2001.

6. Kadiri S: Chronic kidney disease: Sickle cell nephropathy as a likely cause. Annals of Ibadan Postgraduate Med 2006;4:7-10.

7. Day TG, Drasar ER, Fulford T, Sharpe CC, Thein SL. Association between hemolysis and albuminuria in adults with sickle cell anemia. Haematologica. 2012;97(2):201–205.

8. Haymann JP, Stankovic K, Levy P, Avellino V, Tharaux PL, Letavernier E, Grateau G, Baud L, Girot R, Lionnet F. Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis associated feature. Clin J Am Soc Nephrol. 2010;5(5):756–761.

9. Saborio P, Scheinman JI. Sickle cell nephropathy. J Am Soc Nephrol. 1999;10(1):187–192.1999

10. Guasch A. Primer on kidney disease,4th

edition. National Kidney Foundation. Sickle cell Nephropathy.pg 351-355.

11. Johnson CS. Arterial blood pressure and hypervicosity in sickle cell disease. Hematol Oncol Clin North Am 2005;19:827-37.

12. Johnson CS, Giorgio AJ. Arterial blood pressure in adults with sickle cell disease. Arch Intern Med 1981;141:891-3.

13. Grell GA, Alleyne GA, Serjeant GR. Blood pressure in adults with homozygous sickle cell disease. Lancet 1981;2:1166.

14. Pegelow CH, Colangelo L, Steinberg M, Wright EC, Smith J, Phillips G et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med 1997;102:171-7.

15. Karayaylalí I, Onal M, Yíldízer K, Seyrek N, Paydas S, Akoglu E et al. Low blood pressure, decreased incidence of hypertension, and renal cardiac, and autonomic nervous system functions in patients with sickle cell syndromes. Nephron 2002;91:535-7.

16. Ho Chi Hsien, Joao Thomas A. Carvalhaes, Josefina Aparecida P Braga “Blood pressure in Children with sickle cell disease”. Revista Paulista de Pedatria,vol 30(1) Sao Paulo 2012.

17. De Miguel C, Speed JS, Kasztan M, et al. Endothelin-1 and the kidney: new perspectives and recent findings. Curr Opin Nephrol Hypertens. 2016;25(1):35–41

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18. The Fourth Report on the Diagnosis, Evaluation and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics. 2004, vol 114 (2); 555-561.

19. Schwatz GJ, Brion CP, Spitzer A: The use of plasma creatinine concentration for estimating GFR in infants, childrenand adolescents. Pediatr Clin North Am 34:571-590,1987.

20. Epidemiology of Hb Disorders WHO, June 2008 ; Weatherall DJ, Blood 2010.

21. Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol 2006; 17:2228.

22. Aneke J.C,· Adegoke A.O,·Oyekunle A.A et al. Degrees of Kidney Disease in Nigerian Adults with Sickle-Cell Disease. Med Princ Pract 2014;23:271-274 https://doi.org/10.1159/000361029

23. Rakhi P, Naik & Vimal K. Derebail. The spectrum of sickle hemoglobin-related nephropathy: from sickle cell disease to sickle trait, Expert Review of Hematology. 2007; 10:12, 1087-1094, DOI: 10.1080/17474086.2017.1395279

24. Vazquez B, Shah B, Zhang X et al. Hyperfiltration is associated with the development of microalbuminuria in patients with sickle cell anemia. Am J Hematol. 2014 Dec; 89(12): 1156–1157.

25. Sklar AH, Campbell H, Caruana RJ, et al. A population study of renal function in sickle cell anemia. Int J Artif Organs 1990; 13:231.

26. Falk RJ, Scheinman J, Phillips G, et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med 1992; 326:910.

27. Yusuf R, Hassan A, Ibrahim I N, Babadoko A A, Ibinaiye P O. Assessment of kidney function in sickle cell anemia patients in Zaria, Nigeria. Sahel Med J 2017;20:21-5

28. Heilbron DC, Holliday MA, al-Dahwi A,Kogan BA. Expressing glomerular filtration rate in children, Pediatr Nephrol.1991;5:5-11.

29. Olowu WA, Taiwo O, Oyelami A, Durosinmi MA, Adeodu OO, Akinsola A, Ogundipe MO. Glomerular filtration rate in Nigerian children with homozygous sickle cell disease. Niger J Med. 2002 Jan-Mar;11(1):23-5.

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TABLE 1: Age, anthropometric, estimated glomerular filtration rate and blood pressure profile of the

subjects.

Age, anthropometric and blood pressure characteristics

Overall mean ±

Standard deviation

N = 51

Male N = 39

Female

N=12 p value

Age at onset of the study(years)

7.92 ± 4.18 7.72 ± 4.32 8.58 ± 3.78 0.536

Age at diagnosis (years)

4.09 ± 3.33 3.75 ± 5.23 5.19 ± 3.56 0.193

Height (cm) 117.24 ± 22.56 116.56 ± 24.10 119.47 ± 17.34 0.700

Weight (kg) 23.37 ± 9.43 23.13 ± 9.66 24.12 ± 9.00 0.753

Systolic blood pressure (mmHg)

93.21 ± 10.96 94.51 ± 10.86 89.00 ± 10.67 0.129

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Diastolic blood

pressure

(mmHg)

52.08 ± 7.55 52.56 ± 7.21 50.50 ± 8.70 0.413

Mean arterial blood pressure (mmHg)

65.79 ± 7.59 66.56 ± 7.17 63.33 ± 8.67 0.200

Estimated glomerular filtration rate (ml/min/1.73m2)

105.75 ± 35.66 105.12 ± 37.87 107.81 ± 28.61 0.822

TABLE II; ESTIMATED GLOMERULAR FILTRATION RATE OF PATIENTS AND THE PRESENCE OF PROTEINURIA

PROTEINURIA

NEGATIV

E

30MG/D

L

100MG/DL

ESTIMATED GFR

VALUE

>

90mL/min/1.73m2

32 5 1

60-

89mL/min/1.73m2

8 0 0

30-

59mL/min/1.73m2

5 0 0

Total 45 5 1

TABLE III; ESTIMATED GLOMERULAR FILTRATION RATE AND THE PRESENCE OF BLOOD IN THE URINE

BLOOD IN THE URINE

NEGATIVE POSITIVE

ESTIMATED GFR

VALUE

>

90mL/min/1.73m2

37 1

60-

89mL/min/1.73m2

8 0

30-

59mL/min/1.73m2

5 0

Total 50 1

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FIGURE 1

FIGURE 2

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FIGURE 3

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FIGURE 4

FIGURE 5

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FIGURE 6

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TABLE OF AUTHORS Abboud, Miguel R., 12 Abebe, Kaleab Z., 42 Abudulai, Farida, 61 Achebe, Maureen, 24 Adams, Robert, 43 Ahmed, Ibrahim, 62 Ajite, Adebukola, 89 Al Kindi, Salam, 12 Albo, Camila, 72 Alsalman, Abdulkhaliq, 17, 47 Aluc, Aika, 74 Ataga, Kenneth I., 12 Attay, Oguzhan, 13 Axelrod, David, 14 Badamosi, Nnenna, 71 Ballas, Samir K., 76 Barabino, Gilda, 78 Barbetta, Lea, 28 Barnes, Dominik, 71 Barrett, Nadine, 72 Berbaum, M., 16 Berger, Rebecca, 80 Betensky, Marisol, 80 Bharti, PK, 84 Bhor, M., 68 Boccia, Ralph, 40 Bodla, Shankaranand, 33 Bohn, Rhonda, 24 Bonifazi, Fedele, 66 Boosalis, Michael, 52 Bora, Pritam, 72 Boruchov, Donna, 46 Bos, Jennifer, 8 Bowman, Latanya, 72 Bradford, Christopher, 39 Bradford, Sharice, 63 Bridges, Kenneth R., 64 Brigitte A., van Oirschot, 8 Bronté-Hall, Lanetta, 68 Brown, Clark, 12, 61 Brown, LA, 59 Bulone, Linda, 75 Burnett, Arthur, 50 Callaghan, Michael U., 45, 61 Carneiro, Jayanne Moreira, 30 Carvalho, Evanilda Souza de Santana, 28, 30, 79, 86 Cataldo, Vince, 40 Cerqueira, Sheila Santa Barbara, 30 Chan, Flo, 6 Chang, Alicia K., 10

Chern, Irene, 5 Chhabra, Manoj, 53 Clay, E. Leila Jerome, 80 Clifford, Sarah, 61 Cnossen, Marjon H., 8 Cole, Audrey, 38 Cong, Ze, 61 Congdon-Martin, Elisabeth, 14 Corder-Mabe, Joan, 20 Cowden, Emily, 62 Crawford, Albert G., 14 Crawford, Maya, 72 Crouch, Andrew, 35 da Silva, Carlos Alberto Lima, 86 Dada, Opeyemi Kemiki, 73 Dampier, Carlton, 59, 76 Darbari, Deepika, 50 Dauvergne, Bernard, 18 de Montalembert, Mariane, 33 DeNicola, Toni, 25 Desai, Payal, 48, 82 Desai, Rishi J., 24 Diamond, Alan M., 31 Diuguid, David L., 12 Edwards-Elliott, Ronisha, 63 El Beshlawy, Amal, 12 El Rassi, Faud, 83 Elliott, Brian, 33 Elliott, Taylor, 17, 20 El-Rassi, Fuad, 50 Etienne-Julan, Maryse, 18 Evans, Joni, 56 Faller, Douglas V., 36 Fei, Ding-Yu, 17, 47 Ferlis, Mica, 69 Figueroa, J., 59 Flanagan, Jonathan M., 10 Fornari, Eric D., 5 Galacteros, Frédéric, 18 Ganieva, Gulnigor, 53 Gao, Xiufeng, 45 Gavitt, Tyler, 54 George, Deepa, 64 Gershel, Jeffrey, 25 Gladwin, Mark T., 42 Globe, Denise, 24 Gomes, Aline Silva, 86 Gonzalez, Isaiah, 32, 53 Goode, Erin, 46 Gordeuk, V., 16

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Gordeuk, Victor R., 12, 42 Goyal, Ankush, 10 Green, Mykel, 78 Griffith, Jamilla, 27 Gurkan, UA, 84 Gutman, Gail, 25 Guy, Margaret, 69 Haines, Carol, 14 Hakim, Rabia, 32 Halloway, R., 68 Hankins, Jane, 38 Hanstein, Regina, 5 Hardatt, Dianna, 32, 53 Harris, Larri, 62 Hartigan, Sarah, 69 Hasan, MN, 84 Hassab, Hoda, 12 Heeney, Matthew M., 33 Heib, Adele, 5 Hendrick, Clifford, 52 Hines, Patrick, 45 Hodges, Jason, 38 Hong, Lenny K., 31 Hoppe, Carolyn C., 12 Houwing, Maite E., 8 Howard Robin, 64 Howard, Jo, 12 Howard, Kellee, 61 Hrnicek, Amanda, 82 Hsu, Lewis L., 63, 66 Huang, Wenmei, 11 Hulihan, Mary, 74 Ibanez, Vinzon, 31 Intondi, Allison, 12 Inusa, Baba, 66 Iqbal, Nazia Tabassum, 62 Itzep, Nelda, 13 Jacobs-Allen, Sidnie, 73 Jagadeeswaran, Ramasamy, 31 Jain, Shabnam, 51 Jenerette, Coretta Melissa, 30, 86 John, Minnie, 32 Johnson, Shirley, 17, 20, 47 Julie, Kanter, 33 Junker, Louis, 52 Jurek, Marzena, 61 Kanne, Celeste K., 8, 13, 37 Kanter, Julie, 11, 42, 43 Kato, Gregory J., 42, 50, 65 Kaur, Kiranveer, 48 Keates-Baleeiro, Jennifer, 56

Keeler, Colleen N., 73 Keenan, Mary, 27 Kelleman, Michael, 51 Keumeugni, Carlosse, 18 Khemani, Kirshma, 51 Kidwell, Kyle, 72 Knapp, Esther, 67 Kraft, Walter K., 40 Kraut, Eric, 48, 82 Krishnamurti, Lakshmanan, 11, 51, 83 Kulpa, Jolanta, 32, 53 Kumar, R., 84 Kumari, P., 59 Kuo, Kevin, 36 Kurban, Gulriz, 77 Kutlar, Abdullah, 40, 72 Kwiatkowski, Janet L., 11 Lago, Raissa, 28 Lainé, Dramane, 40, 50 Lau, Ching, 46 Le, Vy, 52 Lehrer-Graiwer, Joshua, 12 LeMaire, Sofia M., 77 LeRoux, Rebecca, 36 Levin, Raisa, 24 Li, Biaoru, 52 Lin, X., 68 Lipato, Thokozeni, 17, 47 Lipman, Kelly, 61 Litke, Suzanne, 64 Liu, Ke, 45 Liu, Yang, 53 Loew, Megan, 27 MacDonald, Lindsey, 62 Magee, Lauren Cherry, 69 Mahesri, Mufaddal, 24 Malicki, Joseph, 51 Mallard, Jocelyn, 63 Mann-Jiles, Valerie, 82 Manwani, Deepa, 5 Mapara, Markus Y., 11 Massie, Laura, 67 Mattos, Ivanilde Guedes, 28 McAna, John, 14 McCausland, KL, 68 McClish, Donna, 17, 47 McCracken, Courtney, 51 McGowan, Kerry, 67 McKenzie, Steven, 14 McKerracher, Krista, 24 Melvin, Cathy, 43

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Méndez, G.G., 16 Menka, Grifty, 82 Merino, Raquel, 33 Miller, Alexandra, 11 Miller, Dre, 82 Miller, Robin, 73 Minniti, Caterina, 5, 6, 35, 39, 42 Miodownik, Hope, 39 Molokie, Robert E., 31 Moorman, Spencer, 67 Morris, Claudia R., 42, 51, 59 Morrone, Kerry, 5 Moses, Wendell, 56 Mueller, Martina, 43 Mutebi, Alex, 24 Nandal, S., 68 Narula, Pramod, 53 Nascimento, Helaynne Bezerra, 28 Nduba, Videlis, 12 Nocek, J.M., 16 Nouraie, Seyed M., 65 Odame, Isaac, 33 Ogundare, Ezra, 89 Oh, Alison, 63 Ojo, Bola, 66 Oke, Oluwasola, 89 Olaiya, Oluwaseum, 49 Olatunya, Oladele, 89 Oluwayemi, Oludare, 89 Omoniyi, Evelyn, 89 Pace, Betty, 52, 71 Pace, Betty S., 36 Paikari, Alireza, 10 Parker, Loretta, 56 Pasterkamp, Gerard, 8 Paulose, Jincy, 40, 50, 68 Paulukonis, Susan, 74 Perrine, Susan P., 36, 52 Phillips, Shannon, 43 Pierciey, Francis J., 11 Pope, Michael, 72 Porter, Jerlym, 27, 38 Potthast, Kevin, 80 Pourakbar, Sarah, 49 Pratiwadi, Ramya, 61 Purkayastha, Das, 40, 50 Puthawala, Iram, 82 Quirk, Stephanie Lauren, 66 Rab A.E., Minke, 8 Rafiq, Azhar, 17, 47 Raj, Ashok, 67

Rajasubramaniam, S., 84 Raman, Subha, 48 Rampersaud, Evadnie, 10 Ramphal, Areli, 62 Rash-Ellis, Diana, 73 Rathi, Nityam, 65 Reader, Steve, 73 Rees, David, 33 Rees, Megan, 25 Reisz, Colleen, 49 Ribeil, Jean-Antoine, 11 Riddick-Burden, Gaye, 14 Rivers, Angela, 31, 63 Rivlin, Kenneth, 25 Rizio, A., 68 Rizk, Sanaa, 14 Rocheleau, A., 84 Ross, Diana, 83 Rupff, Rebecca, 27 Russell, Kathryn, 27 Sangerman, Jose, 52 Saulsberry, Anjelica, 38 Schaffler, Mitchell, 78 Schlenz, Alyssa, 43 Schmidt, Manfred, 11 Schneeweiss, Sebastian, 24 Schutgens, Roger E.G., 8 Scrape, Scott, 82 Sebastian, Gracy, 6, 39 Shah, Nirmish, 40 Sheehan, Vivien A., 8, 10, 13, 37 Shelke, Anil, 52 Shiva, S., 59 Shrivas, S., 84 Silva, José Roberto Santos, 86 Silva, Raiotelma Lopes, 28 Silva, Silvone Santa Barbara, 79 Singer, Sylvia T., 36 Sinha, Cynthia, 83 Smith, Wally, 17, 20, 42, 47, 69 Snyder, Angie, 74 Sop, Daniel, 17, 20, 47, 69 Souza, Madlene Oliveira, 79 STERIO-SCD Investigators, 42 Sundaram, Revathy, 32, 53 Szczepanek, Steven M., 54 Takezaki, Mayuko, 52 Tamberou, Cheikh, 18 Tavakoli, Abbas, 86 Taylor VI, James G., 77 Telfer, Paul, 12

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Thomas, Merin, 6, 39 Thompson, Alexis A., 11 Thota, P., 84 Tisdale, John F., 11 Tolorunju, Kayode, 89 Tolu, Seda, 35 Tonda, Margaret, 12 Trouillet Poujol, Valérie, 18 Tsao, David, 13 Tsitsikas, Dimitris A., 12 Ugo, Ugochi O., 5, 6, 35, 39 Uikey, R., 84 Ünal, Selma, 12 van Beers, Eduard J., 8 van Wijk, Richard, 8 Ventura, Lea, 63 Verma, AK, 84 Vichinsky, Elliot, 12 Vinces, Giacomo, 35 Walters, Mark C., 11 Wang, Y., 59

Ward, Lawrence, 14 Ware, Russell E., 12 Watt, A., 59 Weirick, Kimberly, 82 Weiss, Mitchell J., 10 Wells, Leigh, 72 Wen, Fayuan, 77 White, Jennell, 45 White, M., 68 Williams, Robert, 52 Witte, T., 84 Wong, David, 74 Woods, Gerald, 49, 62 Xavier, Aline Silva Gomes, 30 Xu, Hongyan, 72 Ying, Huang, 48 Zhang, Yankai, 10, 37 Zhao, Jun, 67 Zhou, Mei, 74 Zmitrovich, A., 59